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Molefi T, Mabonga L, Hull R, Mwazha A, Sebitloane M, Dlamini Z. The Histomorphology to Molecular Transition: Exploring the Genomic Landscape of Poorly Differentiated Epithelial Endometrial Cancers. Cells 2025; 14:382. [PMID: 40072110 PMCID: PMC11898822 DOI: 10.3390/cells14050382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 03/01/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025] Open
Abstract
The peremptory need to circumvent challenges associated with poorly differentiated epithelial endometrial cancers (PDEECs), also known as Type II endometrial cancers (ECs), has prompted therapeutic interrogation of the prototypically intractable and most prevalent gynecological malignancy. PDEECs account for most endometrial cancer-related mortalities due to their aggressive nature, late-stage detection, and poor response to standard therapies. PDEECs are characterized by heterogeneous histopathological features and distinct molecular profiles, and they pose significant clinical challenges due to their propensity for rapid progression. Regardless of the complexities around PDEECs, they are still being administered inefficiently in the same manner as clinically indolent and readily curable type-I ECs. Currently, there are no targeted therapies for the treatment of PDEECs. The realization of the need for new treatment options has transformed our understanding of PDEECs by enabling more precise classification based on genomic profiling. The transition from a histopathological to a molecular classification has provided critical insights into the underlying genetic and epigenetic alterations in these malignancies. This review explores the genomic landscape of PDEECs, with a focus on identifying key molecular subtypes and associated genetic mutations that are prevalent in aggressive variants. Here, we discuss how molecular classification correlates with clinical outcomes and can refine diagnostic accuracy, predict patient prognosis, and inform therapeutic strategies. Deciphering the molecular underpinnings of PDEECs has led to advances in precision oncology and protracted therapeutic remissions for patients with these untamable malignancies.
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Affiliation(s)
- Thulo Molefi
- Discipline of Obstetrics and Gynaecology, School of Clinical Medicine, University of KwaZulu-Natal, Durban 4002, South Africa;
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP) Pan African Research Institute (PACRI), University of Pretoria, Hartfield, Pretoria 0028, South Africa
- Department of Medical Oncology, University of Pretoria, Hatfield, Pretoria 0028, South Africa
| | - Lloyd Mabonga
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP) Pan African Research Institute (PACRI), University of Pretoria, Hartfield, Pretoria 0028, South Africa
| | - Rodney Hull
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP) Pan African Research Institute (PACRI), University of Pretoria, Hartfield, Pretoria 0028, South Africa
| | - Absalom Mwazha
- Department of Anatomical Pathology, National Health Laboratory Services, Durban 4058, South Africa
| | - Motshedisi Sebitloane
- Discipline of Obstetrics and Gynaecology, School of Clinical Medicine, University of KwaZulu-Natal, Durban 4002, South Africa;
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP) Pan African Research Institute (PACRI), University of Pretoria, Hartfield, Pretoria 0028, South Africa
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Qi Y, Rezaeian AH, Wang J, Huang D, Chen H, Inuzuka H, Wei W. Molecular insights and clinical implications for the tumor suppressor role of SCF FBXW7 E3 ubiquitin ligase. Biochim Biophys Acta Rev Cancer 2024; 1879:189140. [PMID: 38909632 PMCID: PMC11390337 DOI: 10.1016/j.bbcan.2024.189140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/04/2024] [Accepted: 06/17/2024] [Indexed: 06/25/2024]
Abstract
FBXW7 is one of the most well-characterized F-box proteins, serving as substrate receptor subunit of SKP1-CUL1-F-box (SCF) E3 ligase complexes. SCFFBXW7 is responsible for the degradation of various oncogenic proteins such as cyclin E, c-MYC, c-JUN, NOTCH, and MCL1. Therefore, FBXW7 functions largely as a major tumor suppressor. In keeping with this notion, FBXW7 gene mutations or downregulations have been found and reported in many types of malignant tumors, such as endometrial, colorectal, lung, and breast cancers, which facilitate the proliferation, invasion, migration, and drug resistance of cancer cells. Therefore, it is critical to review newly identified FBXW7 regulation and tumor suppressor function under physiological and pathological conditions to develop effective strategies for the treatment of FBXW7-altered cancers. Since a growing body of evidence has revealed the tumor-suppressive activity and role of FBXW7, here, we updated FBXW7 upstream and downstream signaling including FBXW7 ubiquitin substrates, the multi-level FBXW7 regulatory mechanisms, and dysregulation of FBXW7 in cancer, and discussed promising cancer therapies targeting FBXW7 regulators and downstream effectors, to provide a comprehensive picture of FBXW7 and facilitate the study in this field.
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Affiliation(s)
- Yihang Qi
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Abdol-Hossein Rezaeian
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jingchao Wang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Daoyuan Huang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Hong Chen
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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3
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Brown M, Leon A, Kedzierska K, Moore C, Belnoue‐Davis HL, Flach S, Lydon JP, DeMayo FJ, Lewis A, Bosse T, Tomlinson I, Church DN. Functional analysis reveals driver cooperativity and novel mechanisms in endometrial carcinogenesis. EMBO Mol Med 2023; 15:e17094. [PMID: 37589076 PMCID: PMC10565641 DOI: 10.15252/emmm.202217094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/18/2023] Open
Abstract
High-risk endometrial cancer has poor prognosis and is increasing in incidence. However, understanding of the molecular mechanisms which drive this disease is limited. We used genetically engineered mouse models (GEMM) to determine the functional consequences of missense and loss of function mutations in Fbxw7, Pten and Tp53, which collectively occur in nearly 90% of high-risk endometrial cancers. We show that Trp53 deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show that Fbxw7 missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused by Pten loss or Trp53 missense mutation. By transcriptomic analysis, we identify LEF1 signalling as upregulated in Fbxw7/FBXW7-mutant mouse and human endometrial cancers, and in human isogenic cell lines carrying FBXW7 mutation, and validate LEF1 and the additional Wnt pathway effector TCF7L2 as novel FBXW7 substrates. Our study provides new insights into the biology of high-risk endometrial cancer and suggests that targeting LEF1 may be worthy of investigation in this treatment-resistant cancer subgroup.
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Affiliation(s)
- Matthew Brown
- Cancer Genomics and Immunology Group, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
- Oxford NIHR Comprehensive Biomedical Research Centre, Oxford University Hospitals NHS Foundation TrustOxfordUK
| | - Alicia Leon
- Department of PathologyLeiden University Medical CenterLeidenThe Netherlands
| | - Katarzyna Kedzierska
- Cancer Genomics and Immunology Group, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Charlotte Moore
- Cancer Genomics and Immunology Group, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Hayley L Belnoue‐Davis
- Gastrointestinal Stem Cell Biology Laboratory, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Susanne Flach
- Department of Otorhinolaryngology, Head and Neck SurgeryLMU KlinikumMunichGermany
- German Cancer Consortium (DKTK), Partner SiteMunichGermany
| | - John P Lydon
- Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTXUSA
| | - Francesco J DeMayo
- Reproductive and Developmental Biology LaboratoryNational Institute of Environmental Health SciencesResearch Triangle ParkNCUSA
| | - Annabelle Lewis
- Department of Life Sciences, College of Health, Medicine and Life SciencesBrunel University LondonUxbridgeUK
| | - Tjalling Bosse
- Department of PathologyLeiden University Medical CenterLeidenThe Netherlands
| | - Ian Tomlinson
- Institute of Genetics and CancerThe University of EdinburghEdinburghUK
| | - David N Church
- Cancer Genomics and Immunology Group, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
- Oxford NIHR Comprehensive Biomedical Research Centre, Oxford University Hospitals NHS Foundation TrustOxfordUK
- Oxford Cancer Centre, Churchill HospitalOxford University Hospitals Foundation NHS TrustOxfordUK
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4
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Di Fiore R, Suleiman S, Drago-Ferrante R, Subbannayya Y, Suleiman S, Vasileva-Slaveva M, Yordanov A, Pentimalli F, Giordano A, Calleja-Agius J. The Role of FBXW7 in Gynecologic Malignancies. Cells 2023; 12:1415. [PMID: 37408248 DOI: 10.3390/cells12101415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/28/2023] [Accepted: 05/15/2023] [Indexed: 07/07/2023] Open
Abstract
The F-Box and WD Repeat Domain Containing 7 (FBXW7) protein has been shown to regulate cellular growth and act as a tumor suppressor. This protein, also known as FBW7, hCDC4, SEL10 or hAGO, is encoded by the gene FBXW7. It is a crucial component of the Skp1-Cullin1-F-box (SCF) complex, which is a ubiquitin ligase. This complex aids in the degradation of many oncoproteins, such as cyclin E, c-JUN, c-MYC, NOTCH, and MCL1, via the ubiquitin-proteasome system (UPS). The FBXW7 gene is commonly mutated or deleted in numerous types of cancer, including gynecologic cancers (GCs). Such FBXW7 mutations are linked to a poor prognosis due to increased treatment resistance. Hence, detection of the FBXW7 mutation may possibly be an appropriate diagnostic and prognostic biomarker that plays a central role in determining suitable individualized management. Recent studies also suggest that, under specific circumstances, FBXW7 may act as an oncogene. There is mounting evidence indicating that the aberrant expression of FBXW7 is involved in the development of GCs. The aim of this review is to give an update on the role of FBXW7 as a potential biomarker and also as a therapeutic target for novel treatments, particularly in the management of GCs.
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Affiliation(s)
- Riccardo Di Fiore
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
| | - Sherif Suleiman
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta
| | | | - Yashwanth Subbannayya
- School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Sarah Suleiman
- Whipps Cross Hospital, Barts Health NHS Trust, Leytonstone, London E11 1NR, UK
| | - Mariela Vasileva-Slaveva
- Department of Breast Surgery, "Dr. Shterev" Hospital, 1330 Sofia, Bulgaria
- Research Institute, Medical University Pleven, 5800 Pleven, Bulgaria
- Bulgarian Breast and Gynecological Cancer Association, 1784 Sofia, Bulgaria
| | - Angel Yordanov
- Department of Gynecological Oncology, Medical University Pleven, 5800 Pleven, Bulgaria
| | - Francesca Pentimalli
- Department of Medicine and Surgery, LUM University "Giuseppe DeGennaro", 70010 Casamassima, Italy
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
| | - Jean Calleja-Agius
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta
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Stephenson SE, Costain G, Blok LE, Silk MA, Nguyen TB, Dong X, Alhuzaimi DE, Dowling JJ, Walker S, Amburgey K, Hayeems RZ, Rodan LH, Schwartz MA, Picker J, Lynch SA, Gupta A, Rasmussen KJ, Schimmenti LA, Klee EW, Niu Z, Agre KE, Chilton I, Chung WK, Revah-Politi A, Au PB, Griffith C, Racobaldo M, Raas-Rothschild A, Ben Zeev B, Barel O, Moutton S, Morice-Picard F, Carmignac V, Cornaton J, Marle N, Devinsky O, Stimach C, Wechsler SB, Hainline BE, Sapp K, Willems M, Bruel AL, Dias KR, Evans CA, Roscioli T, Sachdev R, Temple SE, Zhu Y, Baker JJ, Scheffer IE, Gardiner FJ, Schneider AL, Muir AM, Mefford HC, Crunk A, Heise EM, Millan F, Monaghan KG, Person R, Rhodes L, Richards S, Wentzensen IM, Cogné B, Isidor B, Nizon M, Vincent M, Besnard T, Piton A, Marcelis C, Kato K, Koyama N, Ogi T, Goh ESY, Richmond C, Amor DJ, Boyce JO, Morgan AT, Hildebrand MS, Kaspi A, Bahlo M, Friðriksdóttir R, Katrínardóttir H, Sulem P, Stefánsson K, Björnsson HT, Mandelstam S, Morleo M, Mariani M, Scala M, Accogli A, Torella A, Capra V, Wallis M, Jansen S, Waisfisz Q, de Haan H, Sadedin S, Lim SC, White SM, Ascher DB, et alStephenson SE, Costain G, Blok LE, Silk MA, Nguyen TB, Dong X, Alhuzaimi DE, Dowling JJ, Walker S, Amburgey K, Hayeems RZ, Rodan LH, Schwartz MA, Picker J, Lynch SA, Gupta A, Rasmussen KJ, Schimmenti LA, Klee EW, Niu Z, Agre KE, Chilton I, Chung WK, Revah-Politi A, Au PB, Griffith C, Racobaldo M, Raas-Rothschild A, Ben Zeev B, Barel O, Moutton S, Morice-Picard F, Carmignac V, Cornaton J, Marle N, Devinsky O, Stimach C, Wechsler SB, Hainline BE, Sapp K, Willems M, Bruel AL, Dias KR, Evans CA, Roscioli T, Sachdev R, Temple SE, Zhu Y, Baker JJ, Scheffer IE, Gardiner FJ, Schneider AL, Muir AM, Mefford HC, Crunk A, Heise EM, Millan F, Monaghan KG, Person R, Rhodes L, Richards S, Wentzensen IM, Cogné B, Isidor B, Nizon M, Vincent M, Besnard T, Piton A, Marcelis C, Kato K, Koyama N, Ogi T, Goh ESY, Richmond C, Amor DJ, Boyce JO, Morgan AT, Hildebrand MS, Kaspi A, Bahlo M, Friðriksdóttir R, Katrínardóttir H, Sulem P, Stefánsson K, Björnsson HT, Mandelstam S, Morleo M, Mariani M, Scala M, Accogli A, Torella A, Capra V, Wallis M, Jansen S, Waisfisz Q, de Haan H, Sadedin S, Lim SC, White SM, Ascher DB, Schenck A, Lockhart PJ, Christodoulou J, Tan TY, Christodoulou J, Tan TY. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome. Am J Hum Genet 2022; 109:601-617. [PMID: 35395208 DOI: 10.1016/j.ajhg.2022.03.002] [Show More Authors] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 02/28/2022] [Indexed: 11/01/2022] Open
Abstract
Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - John Christodoulou
- Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia
| | - Tiong Yang Tan
- Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia.
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Yamashita M, Owa T, Shiraishi R, Adachi T, Ichijo K, Taya S, Miyashita S, Hoshino M. The role of SCF Skp2 and SCF β-TrCP1/2 in the cerebellar granule cell precursors. Genes Cells 2020; 25:796-810. [PMID: 33020978 DOI: 10.1111/gtc.12813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 12/01/2022]
Abstract
A proper balance between proliferation and differentiation of cerebellar granule cell precursors (GCPs) is required for appropriate cerebellar morphogenesis. The Skp1-Cullin1-F-box (SCF) complex, an E3 ubiquitin ligase complex, is involved in polyubiquitination and subsequent degradation of various cell cycle regulators and transcription factors. However, it remains unknown how the SCF complex affects proliferation and differentiation of GCPs. In this study, we found that the scaffold protein Cullin1, and F-box proteins Skp2, β-TrCP1 and β-TrCP2 are expressed in the external granule layer (EGL). Knockdown of these molecules in the EGL showed that Cullin1, Skp2 and β-TrCP2 enhanced differentiation of GCPs. We also observed accumulation of cyclin-dependent kinase inhibitor p27 in GCPs when treated with a Cullin1 inhibitor or proteasome inhibitor. Furthermore, knockdown of p27 rescued enhancement of differentiation by Cullin1 knockdown. These results suggest that the SCF complex is involved in the maintenance of the proliferative state of GCPs through p27 degradation. In addition, inhibition of Cullin1 activity also prevented cell proliferation and enhanced accumulation of p27 in Daoy cells, a cell line derived from the sonic hedgehog subtype of medulloblastoma. This suggested that excess degradation of p27 through the SCF complex causes overproliferation of medulloblastoma cells.
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Affiliation(s)
- Mariko Yamashita
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan
| | - Tomoo Owa
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan
| | - Ryo Shiraishi
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan.,Department of NCNP Brain Function and Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, TMDU, Tokyo, Japan
| | - Toma Adachi
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan.,Department of Life Science and Medical Bioscience, Graduate School of Advance Science and Engineering, TWIns, Waseda University, Tokyo, Japan
| | - Kentaro Ichijo
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan.,Department of Otolaryngology and Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shinichiro Taya
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan
| | - Satoshi Miyashita
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan
| | - Mikio Hoshino
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan
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7
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Park HY, Kwon MJ, Kang HS, Kim YJ, Kim NY, Kim MJ, Min KW, Choi KC, Nam ES, Cho SJ, Park HR, Min SK, Seo J, Choe JY, Lee HK. Targeted next-generation sequencing of well-differentiated rectal, gastric, and appendiceal neuroendocrine tumors to identify potential targets. Hum Pathol 2019; 87:83-94. [DOI: 10.1016/j.humpath.2019.02.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 02/22/2019] [Accepted: 02/24/2019] [Indexed: 01/07/2023]
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FBXW7 in Cancer: What Has Been Unraveled Thus Far? Cancers (Basel) 2019; 11:cancers11020246. [PMID: 30791487 PMCID: PMC6406609 DOI: 10.3390/cancers11020246] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/07/2019] [Accepted: 02/11/2019] [Indexed: 12/14/2022] Open
Abstract
: The FBXW7 (F-box with 7 tandem WD40) protein encoded by the gene FBXW7 is one of the crucial components of ubiquitin ligase called Skp1-Cullin1-F-box (SCF) complex that aids in the degradation of many oncoproteins via the ubiquitin-proteasome system (UPS) thus regulating cellular growth. FBXW7 is considered as a potent tumor suppressor as most of its target substrates can function as potential growth promoters, including c-Myc, Notch, cyclin E, c-JUN, and KLF5. Its regulators include p53, C/EBP-δ, Numb, microRNAs, Pin 1, Hes-5, BMI1, Ebp2. Mounting evidence has indicated the involvement of aberrant expression of FBXW7 for tumorigenesis. Moreover, numerous studies have also shown its role in cancer cell chemosensitization, thereby demonstrating the importance of FBXW7 in the development of curative cancer therapy. This comprehensive review emphasizes on the targets, functions, regulators and expression of FBXW7 in different cancers and its involvement in sensitizing cancer cells to chemotherapeutic drugs.
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Ikenoue T, Terakado Y, Zhu C, Liu X, Ohsugi T, Matsubara D, Fujii T, Kakuta S, Kubo S, Shibata T, Yamaguchi K, Iwakura Y, Furukawa Y. Establishment and analysis of a novel mouse line carrying a conditional knockin allele of a cancer-specific FBXW7 mutation. Sci Rep 2018; 8:2021. [PMID: 29386660 PMCID: PMC5792591 DOI: 10.1038/s41598-018-19769-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 01/08/2018] [Indexed: 12/22/2022] Open
Abstract
F-box and WD40 domain protein 7 (FBXW7) is a component of the SKP1-CUL1-F-box protein (SCF) complex that mediates the ubiquitination of diverse oncogenic target proteins. The exploration of FBXW7 mutations in human primary cancer has revealed three mutation hotspots at conserved arginine residues (Arg465, Arg479, and Arg505) in the WD40 domain, which are critical for substrate recognition. To study the function of human FBXW7R465C, the most frequent mutation in human malignancies, we generated a novel conditional knockin mouse line of murine Fbxw7R468C corresponding to human FBXW7R465C. Systemic heterozygous knockin of the Fbxw7R468C mutation resulted in perinatal lethality due to defects in lung development, and occasionally caused an eyes-open at birth phenotype and cleft palate. Furthermore, mice carrying liver-specific heterozygous and homozygous Fbxw7R468C alleles cooperated with an oncogenic Kras mutation to exhibit bile duct hyperplasia within 8 months of birth and cholangiocarcinoma-like lesions within 8 weeks of birth, respectively. In addition, the substrates affected by the mutant Fbxw7 differed between the embryos, embryonic fibroblasts, and adult liver. This novel conditional knockin Fbxw7R468C line should be useful to gain a more profound understanding of carcinogenesis associated with mutation of FBXW7.
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Affiliation(s)
- Tsuneo Ikenoue
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Yumi Terakado
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Chi Zhu
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Xun Liu
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomoyuki Ohsugi
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Daisuke Matsubara
- Department of Diagnostic Pathology, Jichi Medical University, Shimotsuke, Japan
| | - Tomoki Fujii
- Department of Cancer Genome Research, Sasaki Institute, Sasaki Foundation, Tokyo, Japan
| | - Shigeru Kakuta
- Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Sachiko Kubo
- Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan
| | - Takuma Shibata
- Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,CREST, Japan Science and Technology agency, Kawaguchi, Japan
| | - Kiyoshi Yamaguchi
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoichiro Iwakura
- Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Cheng TH, Thompson DJ, O'Mara TA, Painter JN, Glubb DM, Flach S, Lewis A, French JD, Freeman-Mills L, Church D, Gorman M, Martin L, Hodgson S, Webb PM, Attia J, Holliday EG, McEvoy M, Scott RJ, Henders AK, Martin NG, Montgomery GW, Nyholt DR, Ahmed S, Healey CS, Shah M, Dennis J, Fasching PA, Beckmann MW, Hein A, Ekici AB, Hall P, Czene K, Darabi H, Li J, Dörk T, Dürst M, Hillemanns P, Runnebaum I, Amant F, Schrauwen S, Zhao H, Lambrechts D, Depreeuw J, Dowdy SC, Goode EL, Fridley BL, Winham SJ, Njølstad TS, Salvesen HB, Trovik J, Werner HM, Ashton K, Otton G, Proietto T, Liu T, Mints M, Tham E, Consortium C, Jun Li M, Yip SH, Wang J, Bolla MK, Michailidou K, Wang Q, Tyrer JP, Dunlop M, Houlston R, Palles C, Hopper JL, Peto J, Swerdlow AJ, Burwinkel B, Brenner H, Meindl A, Brauch H, Lindblom A, Chang-Claude J, Couch FJ, Giles GG, Kristensen VN, Cox A, Cunningham JM, Pharoah PDP, Dunning AM, Edwards SL, Easton DF, Tomlinson I, Spurdle AB. Five endometrial cancer risk loci identified through genome-wide association analysis. Nat Genet 2016; 48:667-674. [PMID: 27135401 PMCID: PMC4907351 DOI: 10.1038/ng.3562] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 04/08/2016] [Indexed: 12/18/2022]
Abstract
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
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Affiliation(s)
- Timothy Ht Cheng
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Deborah J Thompson
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Tracy A O'Mara
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Jodie N Painter
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Dylan M Glubb
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Susanne Flach
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Annabelle Lewis
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Juliet D French
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Luke Freeman-Mills
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - David Church
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Maggie Gorman
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Lynn Martin
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Shirley Hodgson
- Department of Clinical Genetics, St George's, University of London, London, UK
| | - Penelope M Webb
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - John Attia
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, NSW, Australia
| | - Elizabeth G Holliday
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, NSW, Australia
| | - Mark McEvoy
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, NSW, Australia
| | - Rodney J Scott
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia
- Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia
- Centre for Information Based Medicine, University of Newcastle, NSW, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
| | - Anjali K Henders
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Nicholas G Martin
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Grant W Montgomery
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Dale R Nyholt
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
| | - Shahana Ahmed
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Catherine S Healey
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Mitul Shah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Joe Dennis
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Peter A Fasching
- University of California at Los Angeles, Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, Los Angeles, CA, USA
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Matthias W Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Alexander Hein
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Arif B Ekici
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Per Hall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Hatef Darabi
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jingmei Li
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Thilo Dörk
- Hannover Medical School, Gynaecology Research Unit, Hannover, Germany
| | - Matthias Dürst
- Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany
| | - Peter Hillemanns
- Hannover Medical School, Clinics of Gynaecology and Obstetrics, Hannover, Germany
| | - Ingo Runnebaum
- Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany
| | - Frederic Amant
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Belgium
| | - Stefanie Schrauwen
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Belgium
| | - Hui Zhao
- Vesalius Research Center, VIB, Leuven, Belgium
- Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Diether Lambrechts
- Vesalius Research Center, VIB, Leuven, Belgium
- Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Jeroen Depreeuw
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Belgium
- Vesalius Research Center, VIB, Leuven, Belgium
- Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Sean C Dowdy
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN, USA
| | - Ellen L Goode
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Brooke L Fridley
- Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Stacey J Winham
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Tormund S Njølstad
- Centre for Cancerbiomarkers, Department of Clinical Science, The University of Bergen, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
| | - Helga B Salvesen
- Centre for Cancerbiomarkers, Department of Clinical Science, The University of Bergen, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
| | - Jone Trovik
- Centre for Cancerbiomarkers, Department of Clinical Science, The University of Bergen, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
| | - Henrica Mj Werner
- Centre for Cancerbiomarkers, Department of Clinical Science, The University of Bergen, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
| | - Katie Ashton
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia
- Centre for Information Based Medicine, University of Newcastle, NSW, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
| | - Geoffrey Otton
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
| | - Tony Proietto
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
| | - Tao Liu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Miriam Mints
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Emma Tham
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Clinical Genetics, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Chibcha Consortium
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- A list of members and affiliations appears in the Supplementary Note
| | - Mulin Jun Li
- Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Shun H Yip
- Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Junwen Wang
- Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Manjeet K Bolla
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Kyriaki Michailidou
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Qin Wang
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Jonathan P Tyrer
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Malcolm Dunlop
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
- MRC Human Genetics Unit, Western General Hospital Edinburgh, Edinburgh, UK
| | - Richard Houlston
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| | - Claire Palles
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Vic, Australia
| | - Julian Peto
- London School of Hygiene and Tropical Medicine, London, UK
| | - Anthony J Swerdlow
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
- Division of Breast Cancer Research, Institute of Cancer Research, London, UK
| | - Barbara Burwinkel
- Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany
- Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Alfons Meindl
- Department of Obstetrics and Gynecology, Division of Tumor Genetics, Technical University of Munich, Munich, Germany
| | - Hiltrud Brauch
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Fergus J Couch
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Vic, Australia
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Vic, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia
| | - Vessela N Kristensen
- Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway
- Department of Clinical Molecular Oncology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway
| | - Angela Cox
- Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK
| | - Julie M Cunningham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Paul D P Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Alison M Dunning
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Stacey L Edwards
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Douglas F Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Ian Tomlinson
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Amanda B Spurdle
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
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11
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Hernandez MA, Patel B, Hey F, Giblett S, Davis H, Pritchard C. Regulation of BRAF protein stability by a negative feedback loop involving the MEK-ERK pathway but not the FBXW7 tumour suppressor. Cell Signal 2016; 28:561-71. [PMID: 26898828 PMCID: PMC6399479 DOI: 10.1016/j.cellsig.2016.02.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 02/08/2016] [Accepted: 02/15/2016] [Indexed: 01/06/2023]
Abstract
The V600EBRAF oncogenic mutation is detected in a wide range of human cancers and induces hyperactivation of the downstream MEK–ERK signalling cascade. Although output of the BRAF–MEK–ERK pathway is regulated by feed-forward RAF activity, feedback control also plays an important role. One such feedback pathway has been identified in Caenorhabditis elegans and involves ERK-mediated phosphorylation of BRAF within a CDC4 phosphodegron (CPD), targeting BRAF for degradation via CDC4 (also known as FBXW7), a component of the SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase complex. Here we investigate this pathway in mammalian cells. Short-term expression of autochthonous V600EBRAF in mouse embryonic fibroblasts (MEFs) leads to down-regulation of BRAF protein levels in a proteasome-dependent manner and V600EBRAF has a reduced half-life compared to WTBRAF in HEK293T cells. These effects were reversed by treatment with the MEK inhibitor PD184352. We have identified the equivalent CPD at residues 400–405 in human BRAF and have found that mutation of ERK phosphorylation sites at residues T401 and S405 in V600EBRAF increases the half-life of the protein. While BRAF and FBXW7 co-immunoprecipitated, the overexpression of FBXW7 did not influence the half-life of either WTBRAF or V600EBRAF. Furthermore, disruption of the substrate-binding site of mouse FBXW7 using the R482Q mutation did not affect the interaction with BRAF and the expression levels of WTBRAF and V600EBRAF were not altered in MEFs derived from mice with the homozygous knockin R482QFBXW7 mutation. Overall these data confirm the existence of a negative feedback pathway by which BRAF protein stability is regulated by ERK. However, unlike the situation in C. elegans, FBXW7 does not play a unique role in mediating subsequent BRAF degradation.
Expression of oncogenic V600EBRAF down-regulates BRAF expression at the protein level. V600EBRAF has a shorter half-life than WTBRAF. BRAF protein stability is subjected to feedback control by the MEK/ERK pathway. This feedback pathway is associated with the oncogene-induced senescence phenotype. ERK phosphorylation sites at T401 and S405 within a conserved CDC4 (FBXW7) phosphodegron of BRAF are involved in the feedback control pathway. The FBXW7 substrate recognition component of the SKP1/CUL1/F-box (SCF) complex binds to BRAF but is not uniquely involved in the regulation of its protein turnover.
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Affiliation(s)
- Maria Aguilar Hernandez
- Department of Molecular Cell Biology, University of Leicester, University Road, Leicester LE1 7RH, UK
| | - Bipin Patel
- Department of Molecular Cell Biology, University of Leicester, University Road, Leicester LE1 7RH, UK
| | - Fiona Hey
- Department of Molecular Cell Biology, University of Leicester, University Road, Leicester LE1 7RH, UK
| | - Susan Giblett
- Department of Molecular Cell Biology, University of Leicester, University Road, Leicester LE1 7RH, UK
| | - Hayley Davis
- Gastrointestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Catrin Pritchard
- Department of Molecular Cell Biology, University of Leicester, University Road, Leicester LE1 7RH, UK; Department of Cancer Studies, University of Leicester, University Road, Leicester LE1 7RH, UK.
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Xu W, Taranets L, Popov N. Regulating Fbw7 on the road to cancer. Semin Cancer Biol 2015; 36:62-70. [PMID: 26459133 DOI: 10.1016/j.semcancer.2015.09.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 09/13/2015] [Indexed: 12/22/2022]
Abstract
The F-box protein Fbw7 targets for degradation critical cellular regulators, thereby controlling essential processes in cellular homeostasis, including cell cycle, differentiation and apoptosis. Most Fbw7 substrates are strongly associated with tumorigenesis and Fbw7 can either suppress or promote tumor development in mouse models. Fbw7 activity is controlled at different levels, resulting in specific and tunable regulation of the abundance and activity of its substrates. Here we highlight recent studies on the role of Fbw7 in controlling tumorigenesis and on the mechanisms that modulate Fbw7 function.
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Affiliation(s)
- Wenshan Xu
- Department of Radiation Oncology and Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Versbacher Str. 5, 97078 Würzburg, Germany
| | - Lyudmyla Taranets
- Department of Radiation Oncology and Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Versbacher Str. 5, 97078 Würzburg, Germany
| | - Nikita Popov
- Department of Radiation Oncology and Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Versbacher Str. 5, 97078 Würzburg, Germany.
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13
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Dependence of Human Colorectal Cells Lacking the FBW7 Tumor Suppressor on the Spindle Assembly Checkpoint. Genetics 2015; 201:885-95. [PMID: 26354767 PMCID: PMC4649658 DOI: 10.1534/genetics.115.180653] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 08/24/2015] [Indexed: 01/24/2023] Open
Abstract
FBW7 (F-box and WD repeat domain containing 7), also known as FBXW7 or hCDC4, is a tumor suppressor gene mutated in a broad spectrum of cancer cell types. As a component of the SCF E3 ubiquitin ligase, FBW7 is responsible for specifically recognizing phosphorylated substrates, many important for tumor progression, and targeting them for ubiquitin-mediated degradation. Although the role of FBW7 as a tumor suppressor is well established, less well studied is how FBW7-mutated cancer cells might be targeted for selective killing. To explore this further, we undertook a genome-wide RNAi screen using WT and FBW7 knockout colorectal cell lines and identified the spindle assembly checkpoint (SAC) protein BUBR1, as a candidate synthetic lethal target. We show here that asynchronous FBW7 knockout cells have increased levels of mitotic APC/C substrates and are sensitive to knockdown of not just BUBR1 but BUB1 and MPS1, other known SAC components, suggesting a dependence of these cells on the mitotic checkpoint. Consistent with this dependence, knockdown of BUBR1 in cells lacking FBW7 results in significant cell aneuploidy and increases in p53 levels. The FBW7 substrate cyclin E was necessary for the genetic interaction with BUBR1. In contrast, the establishment of this dependence on the SAC requires the deregulation of multiple substrates of FBW7. Our work suggests that FBW7 knockout cells are vulnerable in their dependence on the mitotic checkpoint and that this may be a good potential target to exploit in FBW7-mutated cancer cells.
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Zhan P, Wang Y, Zhao S, Liu C, Wang Y, Wen M, Mao JH, Wei G, Zhang P. FBXW7 negatively regulates ENO1 expression and function in colorectal cancer. J Transl Med 2015; 95:995-1004. [PMID: 26097998 PMCID: PMC4552619 DOI: 10.1038/labinvest.2015.71] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Revised: 04/30/2015] [Accepted: 05/04/2015] [Indexed: 11/09/2022] Open
Abstract
FBXW7 (F-box and WD40 domain protein 7) is a tumor suppressor frequently inactivated in human cancers. The precise molecular mechanisms by which FBXW7 exerts antitumor activity remain under intensive investigation and are thought to relate in part to FBXW7-mediated destruction of key cancer-relevant proteins. Enolase 1 (ENO1) possesses oncogenic activity and is often overexpressed in various human cancers, besides its critical role in glycolysis. However, the detailed regulatory mechanisms of ENO1 expression remain unclear. Here we show that the elevated expression of ENO1 was identified in FBXW7-depletion HCT116 cells through two-dimensional protein electrophoresis and mass spectrometry assays (2DE-MS). Subsequent western blotting and immunohistochemical assays confirmed that ENO1 expression reversely correlates with FBXW7 expression in several cells and colon cancer tissues. Furthermore, we show that FBXW7 physically binds to ENO1 and targets ENO1 for ubiquitin-mediated degradation. Functionally, we found that FBXW7 suppresses the ENO1-induced gene expression, lactate production, cell proliferation and migration. These findings suggest that ENO1 is a novel substrate of FBXW7, and its activity can be negatively regulated by FBXW7 at the posttranslational level. Our work provides a novel molecular insight into FBXW7-directed tumor suppression through regulation of ENO1.
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Affiliation(s)
- Panpan Zhan
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Shandong, P.R. China
| | - Yuli Wang
- Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Shandong, P.R. China
| | - Shihu Zhao
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Shandong, P.R. China
| | - Chunyan Liu
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Shandong, P.R. China
| | - Yunshan Wang
- Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Shandong, P.R. China
| | - Mingxin Wen
- Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Shandong, P.R. China
| | - Jian-Hua Mao
- Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
| | - Guangwei Wei
- Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Shandong, P.R. China
| | - Pengju Zhang
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Shandong, P.R. China
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15
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Luan Y, Wang P. FBW7-mediated ubiquitination and degradation of KLF5. World J Biol Chem 2014; 5:216-223. [PMID: 24921010 PMCID: PMC4050114 DOI: 10.4331/wjbc.v5.i2.216] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 01/15/2014] [Accepted: 03/18/2014] [Indexed: 02/05/2023] Open
Abstract
Krüppel-like factor (KLF) family proteins are transcription factors that regulate numerous cellular functions, such as cell proliferation, differentiation, and cell death. Posttranslational modification of KLF proteins is important for their transcriptional activities and biological functions. One KLF family member with important roles in cell proliferation and tumorigenesis is KLF5. The function of KLF5 is tightly controlled by post-translational modifications, including SUMOylation, phosphorylation, and ubiquitination. Recent studies from our lab and others’ have demonstrated that the tumor suppressor FBW7 is an essential E3 ubiquitin ligase that targets KLF5 for ubiquitination and degradation. KLF5 contains functional Cdc4 phospho-degrons (CPDs), which are required for its interaction with FBW7. Mutation of CPDs in KLF5 blocks the ubiquitination and degradation of KLF5 by FBW7. The protein kinase Glycogen synthase kinase 3β is involved in the phosphorylation of KLF5 CPDs. In both cancer cell lines and mouse models, it has been shown that FBW7 regulates the expression of KLF5 target genes through the modulation of KLF5 stability. In this review, we summarize the current progress on delineating FBW7-mediated KLF5 ubiquitination and degradation.
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16
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Davis H, Lewis A, Behrens A, Tomlinson I. Investigation of the atypical FBXW7 mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines. Gut 2014; 63:792-9. [PMID: 23676439 PMCID: PMC3995284 DOI: 10.1136/gutjnl-2013-304719] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Revised: 04/05/2013] [Accepted: 04/20/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVE FBXW7 encodes the substrate recognition component of a ubiquitin ligase that degrades targets such as Notch1, c-Jun, c-Myc and cyclin E. FBXW7 mutations occur in several tumour types, including colorectal cancers. The FBXW7 mutation spectrum in cancers is unusual. Some tumours have biallelic loss of function mutations but most have monoallelic missense mutations involving specific arginine residues at β-propellor tips involved in substrate recognition. DESIGN FBXW7 functional studies have generally used null systems. In order to analyse the most common mutations in human tumours, we created a Fbxw7(fl(R482Q))(/+) mouse and conditionally expressed this mutation in the intestines using Vill-Cre. We compared these mice with heterozygous null (Fbxw7(+/-)) mutants. RESULTS A few sizeable intestinal adenomas occurred in approximately 30% of R482Q/+ and Fbxw7(+/-) mice at age >300 days. Breeding the R482Q allele onto Apc mutant backgrounds led to accelerated morbidity and increased polyp numbers and size. Within the small bowel, polyp distribution was shifted proximally. Elevated levels of two particular Fbxw7 substrates, Klf5 and Tgif1, were found in normal intestine and adenomas of R482Q/+, R482Q/R482Q and Fbxw7(-/-) mice, but not Fbxw7(+/-) animals. On the Apc mutant background, Fbxw7(+/-) mutants had a phenotype intermediate between Fbxw7 wild-type and R482Q/+ mice. CONCLUSIONS Heterozygous Fbxw7 propellor tip (R482Q) mutations promote intestinal tumorigenesis on an Apc mutant background. Klf5 and Tgif1 are strong candidates for mediating this effect. Although heterozygous null Fbxw7 mutations also promote tumour growth, these have a weaker effect than R482Q. These findings explain the FBXW7 mutation spectrum found in human cancers, and emphasise the need for animal models faithfully to reflect human disease.
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Affiliation(s)
- Hayley Davis
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford University, , Oxford, UK
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Abstract
F-box proteins, which are the substrate-recognition subunits of SKP1-cullin 1-F-box protein (SCF) E3 ligase complexes, have pivotal roles in multiple cellular processes through ubiquitylation and subsequent degradation of target proteins. Dysregulation of F-box protein-mediated proteolysis leads to human malignancies. Notably, inhibitors that target F-box proteins have shown promising therapeutic potential, urging us to review the current understanding of how F-box proteins contribute to tumorigenesis. As the physiological functions for many of the 69 putative F-box proteins remain elusive, additional genetic and mechanistic studies will help to define the role of each F-box protein in tumorigenesis, thereby paving the road for the rational design of F-box protein-targeted anticancer therapies.
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Affiliation(s)
- Zhiwei Wang
- 1] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. [2] The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, P. R. China. [3]
| | - Pengda Liu
- 1] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. [2]
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
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Yokobori T, Yokoyama Y, Mogi A, Endoh H, Altan B, Kosaka T, Yamaki E, Yajima T, Tomizawa K, Azuma Y, Onozato R, Miyazaki T, Tanaka S, Kuwano H. FBXW7 mediates chemotherapeutic sensitivity and prognosis in NSCLCs. Mol Cancer Res 2013; 12:32-7. [PMID: 24165483 DOI: 10.1158/1541-7786.mcr-13-0341] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. To improve the prognosis of patients with NSCLCs, new and validated therapeutic targets are critically needed. In this study, we focused on F-box and WD repeat domain containing-7 (FBXW7), an E3 ubiquitin ligase, that regulates the degradation of MCL1, Myc, cyclin E, and TOP2A. Importantly, loss of FBXW7 was associated with increased sensitivity of tumors to a class I-specific histone deacetylase (HDAC) inhibitor, MS-275. Immunohistochemical analysis revealed increased expression of FBXW7 targets, MCL1 and TOP2A, in NSCLC tumors with low expression of FBXW7. Moreover, clinical specimens exhibiting low FBXW7 expression presented with more progressive cancer and significantly shorter cancer-specific survival than patients with high FBXW7 expression. Mechanistic study of NSCLC cell lines with silenced FBXW7 revealed enhanced MS-275 sensitivity and taxol resistance. Interestingly, taxol resistance was eliminated by MS-275 treatment, suggesting the potential of HDAC inhibitors for the treatment of aggressive taxol-resistant NSCLCs that lack FBXW7. IMPLICATIONS FBXW7 status impacts chemosensitivity and is a prognostic marker in NSCLCs. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2013/12/19/1541-7786.MCR-13-0341/F1.large.jpg.
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Affiliation(s)
- Takehiko Yokobori
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showamachi, Maebashi 371-8511 Japan.
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The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell 2013; 153:1552-66. [PMID: 23791182 DOI: 10.1016/j.cell.2013.05.041] [Citation(s) in RCA: 267] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Revised: 03/26/2013] [Accepted: 05/21/2013] [Indexed: 02/06/2023]
Abstract
Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.
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Snyder JL, Kearns CA, Appel B. Fbxw7 regulates Notch to control specification of neural precursors for oligodendrocyte fate. Neural Dev 2012; 7:15. [PMID: 22554084 PMCID: PMC3404928 DOI: 10.1186/1749-8104-7-15] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 05/03/2012] [Indexed: 11/10/2022] Open
Abstract
Background In the developing vertebrate nervous system elevated levels of Notch signaling activity can block neurogenesis and promote formation of glial cells. The mechanisms that limit Notch activity to balance formation of neurons and glia from neural precursors are poorly understood. Results By screening for mutations that disrupt oligodendrocyte development in zebrafish we found one allele, called vu56, that produced excess oligodendrocyte progenitor cells (OPCs). Positional cloning revealed that the vu56 allele is a mutation of fbxw7, which encodes the substrate recognition component of a ubiquitin ligase that targets Notch and other proteins for degradation. To investigate the basis of the mutant phenotype we performed in vivo, time-lapse imaging, which revealed that the increase in OPC number resulted from production of extra OPCs by ventral spinal cord precursors and not from changes in OPC proliferation or death. Notch signaling activity was elevated in spinal cord precursors of fbxw7 mutant zebrafish and inhibition of Notch signaling suppressed formation of excess OPCs. Conclusion Notch signaling promotes glia cell formation from neural precursors in vertebrate embryos. Our data indicate that Fbxw7 helps attenuate Notch signaling during zebrafish neural development thereby limiting the number of OPCs.
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Affiliation(s)
- Julia L Snyder
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
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Addendum. J Pathol 2011. [DOI: 10.1002/path.3966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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