• Cancer
• Cancer therapy
• DCUN1D1
• E3 ligase
• Neddylation

• Humans
• Neoplasms/metabolism
• Neoplasms/drug therapy
• Neoplasms/pathology
• NEDD8 Protein/metabolism
• NEDD8 Protein/genetics
• Ubiquitination
• Protein Processing, Post-Translational
• Signal Transduction/drug effects
• Animals
• Ubiquitin-Protein Ligases/metabolism
• Ubiquitin-Protein Ligases/genetics
• Intracellular Signaling Peptides and Proteins/metabolism
• Intracellular Signaling Peptides and Proteins/genetics

• Cancer Databases
• Drug Discovery
• Genomics
• Immunology
• Metabolomics
• Pharmacoinformatics

• Neoplasms/drug therapy
• Neoplasms/genetics
• Humans
• Drug Discovery
• Computational Biology/methods
• Antineoplastic Agents/therapeutic use
• Databases, Factual
• Software
• Machine Learning

• apoptosis
• autophagy
• high-intensity focused ultrasound
• subcutaneous adipose tissue

• Anti-tumor
• Bioinformatics
• Drug repositioning
• HNSCC
• Parbendazole
• cMap

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Autophagy/drug effects
• Biomarkers, Tumor/genetics
• Bortezomib/pharmacology
• Bortezomib/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Female
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Regulatory Networks/drug effects
• Humans
• MCF-7 Cells
• Organophosphorus Compounds/pharmacology
• Organophosphorus Compounds/therapeutic use
• Receptor, ErbB-2/genetics
• Receptors, Estrogen/genetics
• Receptors, Progesterone/genetics
• Sequence Analysis, RNA
• Sirolimus/pharmacology
• Sirolimus/therapeutic use
• Tamoxifen/pharmacology
• Tamoxifen/therapeutic use
• Trastuzumab/pharmacology
• Trastuzumab/therapeutic use
• Ubiquinone/analogs & derivatives
• Ubiquinone/pharmacology
• Ubiquinone/therapeutic use

• U.S. Food and Drug Administration

Epidermolysis bullosa simplex (EBS) with cardiomyopathy (EBS-KLHL24) is an EBS subtype caused by dominantly inherited, gain-of-function mutations in the gene encoding for the ubiquitin-ligase KLHL24, which addresses specific proteins to proteasomal degradation. EBS-KLHL24 patients are born with extensive denuded skin areas and skin fragility. Whilst skin fragility rapidly ameliorates, atrophy and scarring develop over time, accompanied by life-threatening cardiomyopathy. To date, pathogenetic mechanisms underlying such a unique disease phenotype are not fully characterized. The basal keratin 14 (K14) has been indicated as a KLHL24 substrate in keratinocytes. However, EBS-KLHL24 pathobiology cannot be determined by the mutation-enhanced disruption of K14 alone, as K14 is similarly expressed in foetal and postnatal epidermis and its protein levels are preserved both in vivo and in vitro disease models. In this study, we focused on foetal keratins as additional KLHL24 substrates. We showed that K7, K8, K17 and K18 protein levels are markedly reduced via proteasome degradation in normal foetal keratinocytes transduced with the mutant KLHL24 protein (ΔN28-KLHL24) as compared to control cells expressing the wild-type form. In addition, heat stress led to keratin network defects and decreased resilience in ΔN28-KLHL24 cells. The KLHL24-mediated degradation of foetal keratins could contribute to congenital skin defects in EBS-KLHL24. Furthermore, we observed that primary keratinocytes from EBS-KLHL24 patients undergo accelerated clonal conversion with reduced colony forming efficiency (CFE) and early replicative senescence. Finally, our findings pointed out a reduced CFE in ΔN28-KLHL24-transduced foetal keratinocytes as compared to controls, suggesting that mutant KLHL24 contributes to patients’ keratinocyte clonogenicity impairment.

The transcription factor p73 is a structural and functional homolog of TP53, the most famous and frequently mutated tumor-suppressor gene. The TP73 gene can synthesize an overwhelming number of isoforms via splicing events in 5′ and 3′ ends and alternative promoter usage. Although it originally came into the spotlight due to the potential of several of these isoforms to mimic p53 functions, it is now clear that TP73 has its own unique identity as a master regulator of multifaceted processes in embryonic development, tissue homeostasis, and cancer. This remarkable functional pleiotropy is supported by a high degree of mechanistic heterogeneity, which extends far-beyond the typical mode of action by transactivation and largely relies on the ability of p73 isoforms to form protein–protein interactions (PPIs) with a variety of nuclear and cytoplasmic proteins. Importantly, each p73 isoform carries a unique combination of functional domains and residues that facilitates the establishment of PPIs in a highly selective manner. Herein, we summarize the expanding functional repertoire of TP73 in physiological and oncogenic processes. We emphasize how TP73’s ability to control neurodevelopment and neurodifferentiation is co-opted in cancer cells toward neoneurogenesis, an emerging cancer hallmark, whereby tumors promote their own innervation. By further exploring the canonical and non-canonical mechanistic patterns of p73, we apprehend its functional diversity as the result of a sophisticated and coordinated interplay of: (a) the type of p73 isoforms (b) the presence of p73 interaction partners in the cell milieu, and (c) the architecture of target gene promoters. We suppose that dysregulation of one or more of these parameters in tumors may lead to cancer initiation and progression by reactivating p73 isoforms and/or p73-regulated differentiation programs thereof in a spatiotemporally inappropriate manner. A thorough understanding of the mechanisms supporting p73 functional diversity is of paramount importance for the efficient and precise p73 targeting not only in cancer, but also in other pathological conditions where TP73 dysregulation is causally involved.

• C-terminus
• cancer progression
• development and homeostasis
• differentiation
• gene promoter architecture
• neoneurogenesis
• p73
• protein–protein interactions(PPI)

Recent studies revealed that ethnic differences in mechanistic target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK-1/2) signaling pathways might be associated with the development and progression of different human malignancies. The African American (AA) population has an increased rate of cancer incidence and mortality compared to the Caucasian American (CA) population. Although the socioeconomic differences across different ethnic groups contribute to the disparity in developing different cancers, recent scientific evidence indicates the association of molecular and genetic variations in racial disparities of different human malignancies. The mTOR and ERK-1/2 signaling pathways are one of the well-known oncogenic signaling mechanisms that regulate diverse molecular and phenotypic aspects of normal as well as cancer cells in response to different external or internal stimuli. To date, very few studies have been carried out to explore the significance of racial disparity with abnormal mTOR and ERK-1/2 kinase signaling pathways, which may contribute to the development of aggressive human cancers. In this review, we discuss the differential regulation of mTOR and ERK-1/2 kinase signaling pathways across different ethnic groups, especially between AA and CA populations. Notably, we observed that key signaling proteins associated with mTOR and ERK-1/2 pathway including transforming growth factor-beta (TGF-β), Akt, and VEGFR showed racially disparate expression in cancer patients. Overall, this review article encompasses the significance of racially disparate signaling molecules related to mTOR/ERK1/2 and their potential in developing tailor-made anti-cancer therapies.

• ERK
• MAPK
• cancer
• mTOR
• racial disparity

• Animals
• Autophagy
• Drug Resistance, Neoplasm
• Humans
• Immune System/pathology
• Models, Biological
• Neoplasms/genetics
• Neoplasms/pathology
• Signal Transduction

The tumor suppressor p53 maintains an equilibrium between self-renewal and differentiation to sustain a limited repertoire of stem cells for proper development and maintenance of tissue homeostasis. Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming. A few reports in recent years have indicated that prevalent TP53 oncogenic gain-of-function (GOF) mutations further boosts the stemness properties of cancer cells. In this review, we discuss the role of wild type p53 in regulating pluripotency of normal stem cells and various mechanisms that control the balance between self-renewal and differentiation in embryonic and adult stem cells. We also highlight how inactivating and GOF mutations in p53 stimulate stemness in cancer cells. Further, we have explored the various mechanisms of mutant p53-driven cancer stemness, particularly emphasizing on the non-coding RNA mediated epigenetic regulation. We have also analyzed the association of cancer stemness with other crucial gain-of-function properties of mutant p53 such as epithelial to mesenchymal transition phenotypes and chemoresistance to understand how activation of one affects the other. Given the critical role of cancer stem-like cells in tumor maintenance, cancer progression, and therapy resistance of mutant p53 tumors, targeting them might improve therapeutic efficacy in human cancers with TP53 mutations.

• GOF mutant p53
• cancer stemness
• chemoresistance
• differentiation
• epithelial to mesenchymal transition
• miRNAs
• therapeutic targeting

Inhibiting cell survival and inducing cell death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins and damaged or aged cellular organelles to recycle their constituent metabolites that enable the maintenance of cell survival and genetic stability and even promotes the drug resistance, which severely limits the efficacy of chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect to suppress and promote tumor survival, which makes the effect of targeting autophagy on drug resistance more confusing and fuzzier. In the review, we summarize the regulation of autophagy by emerging ways, the action of targeting autophagy on drug resistance and some of the new therapeutic approaches to treat tumor drug resistance by interfering with autophagy-related pathways. The full-scale understanding of the tumor-associated signaling pathways and physiological functions of autophagy will hopefully open new possibilities for the treatment of tumor drug resistance and the improvement in clinical outcomes.

• Autophagy
• Drug resistance
• Histone deacetylase
• MAPK
• Metabolic stress
• Therapeutic antibody
• miRNA
• p53

• Anticancer targeted therapy
• TAp73
• p53 family
• ΔNp73

• APC activators
• APC inhibitors
• Anaphase Promoting Complex (APC)
• cancer
• protein substrates

Identification of p73 as a structural homolog of p53 fueled early studies aimed at determining if it was capable of performing p53-like functions. This led to a conundrum as p73 was discovered to be hardly mutated in cancers, and yet, TAp73, the full-length form, was found capable of performing p53-like functions, including transactivation of many p53 target genes in cancer cell lines. Generation of mice lacking p73/TAp73 revealed a plethora of developmental defects, with very limited spontaneous tumors arising only at a later stage. Concurrently, novel TAp73 target genes involved in cellular growth promotion that are not regulated by p53 were identified, mooting the possibility that TAp73 may have diametrically opposite functions to p53 in tumorigenesis. We have therefore comprehensively evaluated the TAp73 target genes identified and validated in human cancer cell lines, to examine their contextual relevance. Data from focused studies aimed at appraising if p53 targets are also regulated by TAp73—often by TAp73 overexpression in cell lines with non-functional p53—were affirmative. However, genome-wide and phenotype-based studies led to the identification of TAp73-regulated genes involved in cellular survival and thus, tumor promotion. Our analyses therefore suggest that TAp73 may not necessarily be p53’s natural substitute in enforcing tumor suppression. It has likely evolved to perform unique functions in regulating developmental processes and promoting cellular growth through entirely different sets of target genes that are not common to, and cannot be substituted by p53. The p53-related targets initially reported to be regulated by TAp73 may therefore represent an experimental possibility rather than the reality.

• Cancer cell lines
• TAp73
• p53
• transcriptional targets
• tumor suppression

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Mice
• Nuclear Proteins/genetics
• Nuclear Proteins/metabolism
• Transcription, Genetic
• Tumor Protein p73/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• CMap
• ER stress
• cellular stress
• connectivity map
• drug discovery
• endoplasmic reticulum stress
• hypoxia
• mitochondrial stress
• oxidative stress

• Animals
• Cell Hypoxia/drug effects
• Computer Simulation
• Drug Discovery/methods
• Endoplasmic Reticulum Stress/drug effects
• Heat-Shock Response/drug effects
• Humans
• Mitochondria/drug effects
• Mitochondria/metabolism
• Mitochondria/pathology
• Oxidative Stress/drug effects
• Unfolded Protein Response/drug effects

• autophagy
• cardiovascular diseases
• heart
• hypertrophy
• mice

• AMPK
• cancer
• metformin
• p53
• p63
• p73

Aging may aggravate the damage and dysfunction of different components of multiorgan and thus increasing multiorgan ischemia/reperfusion (IR) injury. IR injury occurs in many organs and tissues, which is a major cause of morbidity and mortality worldwide. The kinase mammalian target of rapamycin (mTOR), an atypical serine/threonine protein kinase, involves in the pathophysiological process of IR injury. In this review, we first briefly introduce the molecular features of mTOR, the association between mTOR and aging, and especially its role on autophagy. Special focus is placed on the roles of mTOR during ischemic and IR injury. We then clarify the association between mTOR and conditioning phenomena. Following this background, we expand our discussion to potential future directions of research in this area. Collectively, information reviewed herein will serve as a comprehensive reference for the actions of mTOR in IR injury and may be significant for the design of future research and increase the potential of mTOR as a therapeutic target.

• Aging
• Autophagy
• Ischemia/reperfusion injury
• mTOR

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors (TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.

• Alternative isoforms
• Transcription factors
• Hepatocellular carcinoma
• Alternative splicing
• Hepatic differentiation
• Personalized treatment

We report that p73 is expressed in ovarian granulosa cells and that loss of p73 leads to attenuated follicle development, ovulation, and corpus luteum formation, resulting in decreased levels of circulating progesterone and defects in mammary gland branching. Ectopic progesterone in p73-deficient mice completely rescued the mammary branching and partially rescued the ovarian follicle development defects. Performing RNA sequencing (RNA-seq) on transcripts from murine wild-type and p73-deficient antral follicles, we discovered differentially expressed genes that regulate biological adhesion programs. Through modulation of p73 expression in murine granulosa cells and transformed cell lines, followed by RNA-seq and chromatin immunoprecipitation sequencing, we discovered p73-dependent regulation of a gene set necessary for cell adhesion and migration and components of the focimatrix (focal intra-epithelial matrix), a basal lamina between granulosa cells that promotes follicle maturation. In summary, p73 is essential for ovarian folliculogenesis and functions as a key regulator of a gene network involved in cell-to-cell adhesion and migration.

•

p73 is required for murine ovarian folliculogenesis and proper corpus luteum formation

• Developmental Biology
• Functional Aspects of Cell Biology
• Molecular Network
• Omics

• autophagy
• histone deacetylase inhibitor
• mTOR
• p53
• suberoylanilide hydroxamic acid
• tumor

• Animals
• Apoptosis
• Autophagy
• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Tumor Suppressor Protein p53/metabolism

• autophagy
• chemotherapy
• cisplatin
• osteosarcoma (OS)

• Functional genomics
• chemical biology
• gene expression profiling

Autophagy is an essential process of the eukaryotic cell allowing degradation and recycling of dysfunctional cellular components in response to either physiological or pathological changes. Inhibition of autophagy in combination with chemotherapeutic treatment has emerged as a novel approach in cancer treatment leading to cell cycle arrest, differentiation, and apoptosis. Suberoyl hydroxamic acid (SAHA) is a broad-spectrum histone deacetylase inhibitor (HDACi) suppressing family members in multiple HDAC classes. Increasing evidence indicates that SAHA and other HDACi can, in addition to mitochondria-mediated apoptosis, also promote caspase-independent autophagy. SAHA-induced mTOR inactivation as a major regulator of autophagy activating the remaining autophagic core machinery is by far the most reported pathway in several tumor models. However, the question of which upstream mechanisms regulate SAHA-induced mTOR inactivation that consequently initiate autophagy has been mainly left unexplored. To elucidate this issue, we recently initiated a study clarifying different modes of SAHA-induced cell death in two human uterine sarcoma cell lines which led to the conclusion that the tumor suppressor protein p53 could act as a molecular switch between SAHA-triggered autophagic or apoptotic cell death. In this review, we present current research evidence about HDACi-mediated apoptotic and autophagic pathways, in particular with regard to p53 and its therapeutic implications.

• Apoptosis
• Autophagy
• HDAC
• HDACi
• SAHA
• Tumor
• p53

• Autophagy
• Lysosome
• Transcription

• Chondrocyte
• FGFR3
• Osteoarthritis
• PPR
• mTORC1

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with poor prognosis and is enriched in cancer stem cells (CSCs). However, it is not completely understood how the CSCs were maintained in TNBC. In this study, by analyzing The Cancer Genome Atlas (TCGA) provisional datasets and several small-size breast datasets, we found that cadherins (CDHs) 2, 4, 6, and 17 were frequently amplified/overexpressed in 47% of TNBC while E-cadherin (CDH1) was downregulated/mutated at 10%. The alterations of CDH2/4/6/17 were strongly associated with the elevated levels of several stem cell-related transcription factors (SC-TFs) including FOXM1, MCM2, WWTR1, SNAI1, and SOX9. CDH2/4/6/17-enriched genes including FOXM1 and MCM2 were also clustered and regulated by NFY (nuclear transcription factor Y) and/or EVI1/MECOM. Meanwhile, these SC-TFs including NFYA were upregulated in TNBC cells, but they were downregulated in luminal type of cells. Furthermore, small compounds might be predicted via the Connectivity Map analysis to target TNBC with the alterations of CDH2/4/6/17 and SC-TFs. Together with the important role of these SC-TFs in the stem cell regulation, our data provide novel insights into the maintenance of CSCs in TNBC and the discovery of these SC-TFs associated with the alterations of CDH2/4/6/17 has an implication in targeted therapy of TNBC.

• Epstein-Barr virus
• apoptosis/cell death
• gastrointestinal analysis
• tumor suppressor genes

Cranberries are rich in bioactive constituents known to improve urinary tract health and more recent evidence supports cranberries possess cancer inhibitory properties. However, mechanisms of cancer inhibition by cranberries remain to be elucidated, particularly in vivo. Properties of a purified cranberry-derived proanthocyanidin extract (C-PAC) were investigated utilizing acid-sensitive and acid-resistant human esophageal adenocarcinoma (EAC) cell lines and esophageal tumor xenografts in athymic NU/NU mice. C-PAC induced caspase-independent cell death mainly via autophagy and low levels of apoptosis in acid-sensitive JHAD1 and OE33 cells, but resulted in cellular necrosis in acid-resistant OE19 cells. Similarly, C-PAC induced necrosis in JHAD1 cells pushed to acid-resistance via repeated exposures to an acidified bile cocktail. C-PAC associated cell death involved PI3K/AKT/mTOR inactivation, pro-apoptotic protein induction (BAX, BAK1, deamidated BCL-xL, Cytochrome C, PARP), modulation of MAPKs (P-P38/P-JNK) and G_2-M cell cycle arrest in vitro. Importantly, oral delivery of C-PAC significantly inhibited OE19 tumor xenograft growth via modulation of AKT/mTOR/MAPK signaling and induction of the autophagic form of LC3B supporting in vivo efficacy against EAC for the first time. C-PAC is a potent inducer of EAC cell death and is efficacious in vivo at non-toxic behaviorally achievable concentrations, holding promise for preventive or therapeutic interventions in cohorts at increased risk for EAC, a rapidly rising and extremely deadly malignancy.

• PI3K/AKT/mTOR
• autophagy
• bile acid
• cranberry proanthocyanidins
• esophageal adenocarcinoma

• Autophagy
• Target gene
• Therapy
• Tumorigenesis
• p53

• Autophagy
• Cell survival
• Heart
• Ischemia-reperfusion injury

• CK2, Casein Kinase 2
• CSC, Cancer Stem Cells
• DMAT, 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole
• HEKA, Human epidermal keratinocytes
• HNSCC, Head and neck squamous cell carcinoma
• HOK, Human oral keratinocytes
• SP, Side population
• TAp73, Transactivating p73
• TP53, Transforming Protein p53
• UM-SCC, University of Michigan Squamous Cell Carcinoma
• mt, Mutant
• wt, Wild-type

• Benzimidazoles/pharmacology
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Casein Kinase II/antagonists & inhibitors
• Casein Kinase II/metabolism
• Cell Line, Tumor
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Enzyme Inhibitors/pharmacology
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms/genetics
• Head and Neck Neoplasms/metabolism
• Head and Neck Neoplasms/pathology
• Homeodomain Proteins/genetics
• Humans
• Mutation
• Nanog Homeobox Protein
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Nuclear Proteins/genetics
• Nuclear Proteins/metabolism
• Octamer Transcription Factor-3/genetics
• Phosphorylation
• RNA, Small Interfering/pharmacology
• SOXB1 Transcription Factors/genetics
• Squamous Cell Carcinoma of Head and Neck
• Threonine/metabolism
• Tumor Protein p73
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism

• Z01 DC000016 Intramural NIH HHS
• Z01 DC000073 Intramural NIH HHS
• Howard Hughes Medical Institute
• Z01-DC-000016 NIDCD NIH HHS

Drug repositioning is a popular approach in the pharmaceutical industry for identifying potential new uses for existing drugs and accelerating the development time. Non-small-cell lung cancer (NSCLC) is one of the leading causes of death worldwide. To reduce the biological heterogeneity effects among different individuals, both normal and cancer tissues were taken from the same patient, hence allowing pairwise testing. By comparing early- and late-stage cancer patients, we can identify stage-specific NSCLC genes. Differentially expressed genes are clustered separately to form up- and downregulated communities that are used as queries to perform enrichment analysis. The results suggest that pathways for early- and late-stage cancers are different. Sets of up- and downregulated genes were submitted to the cMap web resource to identify potential drugs. To achieve high confidence drug prediction, multiple microarray experimental results were merged by performing meta-analysis. The results of a few drug findings are supported by MTT assay or clonogenic assay data. In conclusion, we have been able to assess the potential existing drugs to identify novel anticancer drugs, which may be helpful in drug repositioning discovery for NSCLC.

• cellular biophysics
• lung
• cancer
• drugs
• genetics
• tumours
• lab‐on‐a‐chip
• proteins
• molecular biophysics
• graph theory
• query processing
• medical computing
• down‐regulated gene expression
• up‐regulated gene expression
• potential target genes
• drugbank
• potential drugs
• connectivity map web resource
• biological processes
• functional enrichment analysis
• up‐regulated communities
• down‐regulated communities
• cancer‐associated protein complexes
• k‐communities
• highly‐dense modules
• ppin
• graph theory analysis
• lung cancer protein‐protein interaction network
• mips
• biogrid
• arrayexpress
• microarray
• nontumour tissues
• human lung adenocarcinoma tumour
• bioconductor package
• tumour suppressor protein
• oncoprotein
• nonsmall cell lung cancer
• in silico identification

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents/chemistry
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Cell Line, Tumor
• Cell Survival
• Cluster Analysis
• Computational Biology/methods
• Computer Simulation
• Drug Discovery
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Middle Aged
• Oligonucleotide Array Sequence Analysis/methods
• Signal Transduction
• Technology, Pharmaceutical

• National Science Council of Taiwan

• autophagy
• heart
• hypertrophy
• ischemia
• mechanistic target of rapamycin complex 1
• metabolism
• sirolimus

• TP53
• TP63
• TP73
• cellular metabolism
• microRNA
• p53
• p63
• p73
• ubiquitylation

• Animals
• Cell Line, Tumor
• Cytoskeletal Proteins/metabolism
• DNA-Binding Proteins/metabolism
• DNA-Binding Proteins/physiology
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Melanoma/metabolism
• Melanoma/pathology
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Transplantation
• Nuclear Proteins/metabolism
• Nuclear Proteins/physiology
• Proto-Oncogene Proteins c-akt/metabolism
• Receptor, IGF Type 1/metabolism
• STAT3 Transcription Factor/metabolism
• Signal Transduction
• Skin Neoplasms/metabolism
• Skin Neoplasms/pathology
• Tumor Protein p73
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Proteins/metabolism
• Tumor Suppressor Proteins/physiology

• B-cell receptor
• TP63
• chronic lymphocytic leukaemia
• methylation

The tumor suppressor p53 was previously shown to markedly up-regulate the expression of the PRODH gene, encoding the proline dehydrogenase (PRODH) enzyme, which catalyzes the first step in proline degradation. Also PRODH2, which degrades 4-hydroxy-L-proline, a product of protein (e.g. collagen) catabolism, was recently described as a p53 target. Here, we confirmed p53-dependent induction of endogenous PRODH in response to genotoxic damage in cell lines of different histological origin. We established that over-expression of TAp73β or TAp63β is sufficient to induce PRODH expression in p53-null cells and that PRODH expression parallels the modulation of endogenous p73 by genotoxic drugs in several cell lines. The p53, p63, and p73-dependent transcriptional activation was linked to specific intronic response elements (REs), among those predicted by bioinformatics tools and experimentally validated by a yeast-based transactivation assay. p53 occupancy measurements were validated in HCT116 and MCF7 human cell lines. Conversely, PRODH2 was not responsive to p63 nor p73 and, at best, could be considered a weak p53 target. In fact, minimal levels of PRODH2 transcript induction by genotoxic stress was observed exclusively in one of four p53 wild-type cell lines tested. Consistently, all predicted p53 REs in PRODH2 were poor matches to the p53 RE consensus and showed very weak responsiveness, only to p53, in the functional assay. Taken together, our results highlight that PRODH, but not PRODH2, expression is under the control of p53 family members, specifically p53 and p73. This supports a deeper link between proteins of the p53-family and metabolic pathways, as PRODH modulates the balance of proline and glutamate levels and those of their derivative alpha-keto-glutarate (α-KG) under normal and pathological (tumor) conditions.

• Base Sequence
• Binding Sites/genetics
• DNA Damage/genetics
• HCT116 Cells
• Humans
• Introns/genetics
• MCF-7 Cells
• Molecular Sequence Data
• Proline Oxidase/genetics
• Proline Oxidase/metabolism
• Protein Binding/genetics
• Protein Stability
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Response Elements/genetics
• Saccharomyces cerevisiae/metabolism
• Transcription Factors/metabolism
• Transcriptional Activation/genetics
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Proteins/metabolism