• crispr-cas9 genome editing
• genetic engineering
• cancer models

• Animals
• Mice
• CRISPR-Cas Systems/genetics
• Gene Editing/methods
• Gene Knock-In Techniques/methods
• Endodeoxyribonucleases/genetics
• Endodeoxyribonucleases/metabolism
• Genetic Engineering/methods
• Bacterial Proteins/genetics
• Bacterial Proteins/metabolism
• Acidaminococcus/genetics
• Acidaminococcus/enzymology
• CRISPR-Associated Proteins/genetics
• CRISPR-Associated Proteins/metabolism
• Fibroblasts/metabolism
• Lymphoma/genetics

• cancer models
• in vitro models
• in‐vivo model

• Animals
• Humans
• Neoplasms/pathology
• Neoplasms/genetics
• Neoplasms/drug therapy
• Neoplasms/therapy
• Mice
• Tumor Microenvironment
• Disease Models, Animal
• Disease Progression
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use

• RNAi
• SiRNA
• aptamer
• cancer therapeutics
• m-RNA vaccine.
• miRNA

• Humans
• Neoplasms/therapy
• Neoplasms/genetics
• Animals
• RNA, Small Interfering/therapeutic use
• RNA, Small Interfering/genetics
• RNA Interference
• Antineoplastic Agents/therapeutic use
• MicroRNAs/genetics

• B-lymphoma
• LAPTM5
• c-Myc
• miR-17-3p

• Humans
• Animals
• Mice
• 3' Untranslated Regions/genetics
• Burkitt Lymphoma/metabolism
• Transcription Factors/genetics
• Lymphoma, Large B-Cell, Diffuse/genetics
• MicroRNAs/genetics
• Membrane Proteins/genetics

• Apoptosis
• Biomarkers
• Cancer therapy
• LncRNAs
• Therapeutic target

Impaired p53 function is one of the central molecular features of a tumor cell and even a partial reduction in p53 activity can increase the cancer risk in mice and men. From a therapeutic perspective it is noteworthy that tumor cells often become addicted to the absence of p53 providing a rationale for developing p53 reactivating compounds to treat cancer patients. Unfortunately, many of the compounds that are currently undergoing preclinical and clinical testing fail to fully reactivate mutant p53 proteins, raising the crucial question: how much p53 activity is needed to elicit a therapeutic effect?

We have genetically modelled partial p53 reactivation using knock-in mice with inducible expression of the p53 variant E177R. This variant has a reduced ability to bind and transactivate target genes and consequently causes moderate cancer susceptibility. We have generated different syngeneically transplanted and autochthonous mouse models of p53-deficient acute myeloid leukemia and B or T cell lymphoma. After cancer manifestation we have activated E177R expression and analyzed the in vivo therapy response by bioluminescence or magnetic resonance imaging. The molecular response was further characterized in vitro by assays for gene expression, proliferation, senescence, differentiation, apoptosis and clonogenic growth.

We report the conceptually intriguing observation that the p53 variant E177R, which promotes de novo leukemia and lymphoma formation, inhibits proliferation and viability, induces immune cell infiltration and triggers cancer regression in vivo when introduced into p53-deficient leukemia and lymphomas. p53-deficient cancer cells proved to be so addicted to the absence of p53 that even the low-level activity of E177R is detrimental to cancer growth.

The observation that a partial loss-of-function p53 variant promotes tumorigenesis in one setting and induces regression in another, underlines the highly context-specific effects of individual p53 mutants. It further highlights the exquisite sensitivity of cancer cells to even small changes in p53 activity and reveals that changes in activity level are more important than the absolute level. As such, the study encourages ongoing research efforts into mutant p53 reactivating drugs by providing genetic proof-of-principle evidence that incomplete p53 reactivation may suffice to elicit a therapeutic response.

The online version contains supplementary material available at 10.1186/s13046-022-02269-6.

• Leukemia
• Lymphoma
• Molecular therapy
• Mouse models
• Tumor suppressor gene
• p53
• p53 reactivation

Manipulation of gene activity through creation of hypomorphic mutants has been a long-standing tool in examining gene function. Our previous studies have indicated that hypomorphic mutants could be created by inserting cis-regulatory sequences composed of consecutive adenosine nucleotides called poly(A) tracks. Here we use poly(A) tracks to create hypomorphic mutants and functional characterization of membrane, secretory, and endogenous proteins. Insertion of poly(A) tracks into the sequences of interleukin-2 and membrane protein CD20 results in a programmable reduction of mRNA stability and attenuation of protein expression regardless of the presence of a signaling sequence. Likewise, CRISPR-Cas9 targeted insertion of poly(A) tracks into the coding sequence of the endogenous human genes AUF1 and TP53 results in a programmable reduction of targeted protein and mRNA levels. Functional analyses of AUF1-engineered hypomorphs indicate a direct correlation between AUF1 gene levels and the stability of AUF1-regulated mRNAs. Hypomorphs of TP53 affect expression of the target genes differentially depending on the severity of the hypomorphic mutation. Finally, decreases in TP53 protein affect the same cellular pathways in poly(A) track-engineered cells as in cancer cells, indicating these variants’ biological relevance. These results highlight this technology’s power to create predictable, stable hypomorphs in recombinant or endogenous genes in combination with CRISPR-Cas9 engineering tools.

• AUF1
• CD20
• IL2
• TP53
• gene regulation
• hypomorphs
• mRNA
• membrane proteins
• polyA track
• secretory proteins

• P30 CA091842 NCI NIH HHS
• R01 GM112824 NIGMS NIH HHS
• R01 GM136823 NIGMS NIH HHS
• R01 MH116999 NIMH NIH HHS

Cancer genome sequencing has identified dozens of mutations with a putative role in lymphomagenesis and leukemogenesis. Validation of driver mutations responsible for B cell neoplasms is complicated by the volume of mutations worthy of investigation and by the complex ways that multiple mutations arising from different stages of B cell development can cooperate. Forward and reverse genetic strategies in mice can provide complementary validation of human driver genes and in some cases comparative genomics of these models with human tumors has directed the identification of new drivers in human malignancies. We review a collection of forward genetic screens performed using insertional mutagenesis, chemical mutagenesis and exome sequencing and discuss how the high coverage of subclonal mutations in insertional mutagenesis screens can identify cooperating mutations at rates not possible using human tumor genomes. We also compare a set of independently conducted screens from Pax5 mutant mice that converge upon a common set of mutations observed in human acute lymphoblastic leukemia (ALL). We also discuss reverse genetic models and screens that use CRISPR-Cas, ORFs and shRNAs to provide high throughput in vivo proof of oncogenic function, with an emphasis on models using adoptive transfer of ex vivo cultured cells. Finally, we summarize mouse models that offer temporal regulation of candidate genes in an in vivo setting to demonstrate the potential of their encoded proteins as therapeutic targets.

• B cell leukemia
• B cell lymphoma
• CRISPR-Cas
• exome sequencing
• insertional mutagenesis
• mouse models
• reverse genetics
• shRNA

• RNA interference
• RNAi
• cancer dependencies
• functional genomics
• shRNA
• siRNA

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Disease Progression
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Silencing
• Humans
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/genetics
• Oncogene Proteins/genetics
• RNA Interference
• Tumor Suppressor Proteins/genetics

• ZIA BC011704 Intramural NIH HHS
• National Cancer Institute

• BXV1 xenotropic retrovirus
• EndoC-β H2 cells
• Pancreatic β cell lines
• Rat insulin promoter
• SIN γ-retrovector
• TVA gesicles
• α-Retrovector

• cancer
• lncRNA
• p53
• therapy

• Animals
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Carcinogenesis/metabolism
• Cell Proliferation/genetics
• Cells, Cultured
• Class Ia Phosphatidylinositol 3-Kinase/genetics
• Class Ia Phosphatidylinositol 3-Kinase/metabolism
• Female
• Glioblastoma/metabolism
• Glioblastoma/pathology
• Heterografts
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• PTEN Phosphohydrolase/metabolism
• Phosphotransferases (Alcohol Group Acceptor)/genetics
• Phosphotransferases (Alcohol Group Acceptor)/metabolism
• RNA Interference
• Transduction, Genetic
• Tumor Burden/genetics

• R01 CA190957 NCI NIH HHS
• R01 CA223370 NCI NIH HHS
• R01 NS082312 NINDS NIH HHS
• R56 NS095822 NINDS NIH HHS
• Korea Health Industry Development Institute
• National Institutes of Health

• DINO
• NR2E3
• long noncoding RNA
• p53

• cancer
• cell stress
• gene knockout
• p53
• posttranslational regulation
• protein phosphatase 5
• protein phosphorylation
• protein serine/threonine phosphatase (PSP)
• transcriptional regulation
• tumorigenesis

• CRISPR/Cas9
• genetically engineered mouse models
• humanized mouse models
• non-germline genetically engineered mouse models
• patient-derived xenograft models
• transgenic mice

Mutations in members of the SWI/SNF chromatin remodeling family are common events in cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the mouse pancreas in the setting of oncogenic Kras^G12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained Kras^G12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with Kras^G12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.

The pancreas produces many different hormones, as well as several substances important for digestion. To perform these roles, the pancreas contains different types of cells; for example, acinar cells make digestive enzymes that help to break down food. But, like other cells in the body, pancreatic cells can accumulate mutations in their DNA that cause them to divide, acquire an altered identity and form a cancerous tumor.

The DNA of cells is packed into a structure called chromatin. While the DNA sequence is essentially the same across all normal cells of a given individual, chromatin can be more or less compacted in the different cell types that comprise our body tissues. A collection of proteins called the SWI/SNF complex can reorganize the chromatin to change how tightly the DNA is packed. This determines which genes in the DNA are accessible and can be activated, and which ones cannot.

Around 25% of pancreatic cancers contain mutations in genes that produce proteins of the SWI/SNF complex. These mutations normally occur with an additional mutation that over-activates the gene that produces a potentially cancer-causing protein called Kras. Livshits et al. have now genetically engineered mice to investigate how one such SWI/SNF complex protein, called Arid1a, affects how pancreatic cancer develops using a genetic approach that made possible to temporarily halt the production of Arid1a in acinar cells by feeding these mice an antibiotic. The gene that produces Kras was also over-activated in the pancreases of the mice, making them more likely to develop cancer.

Within just two weeks of stopping the production of Arid1a, the acinar cells stopped producing digestive enzymes and started making other proteins that are typically found in cancerous cells, indicating that Arid1a is involved in maintaining the normal identity and activity of these cells. Restoring the ability of altered acinar cells to produce normal levels of Arid1a (by removing the mice from the antibiotic diet) did not reverse these changes. Biochemical experiments showed that acinar cells with reduced levels of Arid1a have altered chromatin. In particular, the genes that produce digestive enzymes, which are normally active in healthy pancreases, were less accessible in mice who had over-active Kras and reduced levels of Arid1a.

The results presented by Livshits et al. provide the first evidence of how alterations to Arid1a can lead to irreversible changes in the identity and activity of pancreatic acinar cells. These results will need to be carefully considered by researchers who are developing treatments for cancer patients with mutations in Arid1a and other SWI/SNF proteins. In particular, methods that attempt to restore the functions of absent SWI/SNF proteins to cancer cells are unlikely to treat the cancer successfully.

• RNAi
• SWI/SNF
• acinar cell
• cancer biology
• mouse
• mouse model
• pancreas cancer
• plasticity

• Patisiran
• RNAi
• TTR amyloidosis
• TTR gene
• gene silencing
• siRNA

Genetically engineered mouse models (GEMMs) have contributed significantly to the field of cancer research. In contrast to cancer cell inoculation models, GEMMs develop de novo tumors in a natural immune‐proficient microenvironment. Tumors arising in advanced GEMMs closely mimic the histopathological and molecular features of their human counterparts, display genetic heterogeneity, and are able to spontaneously progress toward metastatic disease. As such, GEMMs are generally superior to cancer cell inoculation models, which show no or limited heterogeneity and are often metastatic from the start. Given that GEMMs capture both tumor cell‐intrinsic and cell‐extrinsic factors that drive de novo tumor initiation and progression toward metastatic disease, these models are indispensable for preclinical research. GEMMs have successfully been used to validate candidate cancer genes and drug targets, assess therapy efficacy, dissect the impact of the tumor microenvironment, and evaluate mechanisms of drug resistance. In vivo validation of candidate cancer genes and therapeutic targets is further accelerated by recent advances in genetic engineering that enable fast‐track generation and fine‐tuning of GEMMs to more closely resemble human patients. In addition, aligning preclinical tumor intervention studies in advanced GEMMs with clinical studies in patients is expected to accelerate the development of novel therapeutic strategies and their translation into the clinic.

• cancer
• genetically engineered mouse models
• metastasis
• therapy
• tumor microenvironment

RNA interference (RNAi) is a powerful tool for the study of gene function in mammalian systems, including transgenic mice. Here, we report a gene knockdown system based on the human mir-187 precursor. We introduced small interfering RNA (siRNA) sequences against the mouse melanocortin-4 receptor (mMc4r) to alter the targeting of miR-187. The siRNA-expressing cassette was placed under the control of the cytomegalovirus (CMV) early enhancer/chicken β-actin promoter. In vitro, the construct efficiently knocked down the gene expression of a co-transfected mMc4r-expression vector in cultured mammalian cells. Using this construct, we generated a transgenic mouse line which exhibited partial but significant knockdown of mMc4r mRNA in various brain regions. Northern blot analysis detected transgenic expression of mMc4r siRNA in these regions. Furthermore, the transgenic mice fed a normal diet ate 9% more and were 30% heavier than wild-type sibs. They also developed hyperinsulinemia and fatty liver as do mMc4r knockout mice. We determined that this siRNA expression construct based on mir-187 is a practical and useful tool for gene functional studies in vitro as well as in vivo.

• Animals
• Cell Line
• DNA Damage
• Feedback, Physiological
• Female
• Humans
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• RNA, Long Noncoding/physiology
• Rats
• Signal Transduction
• Tumor Suppressor Protein p53/metabolism

• T32 CA009302 NCI NIH HHS
• R01 HG004361 NHGRI NIH HHS
• DP1 HD075622 NICHD NIH HHS
• K12 GM081266 NIGMS NIH HHS
• P50 GM107615 NIGMS NIH HHS
• T32 HG000044 NHGRI NIH HHS
• R01 ES023168 NIEHS NIH HHS
• R01 CA118750 NCI NIH HHS
• P30 CA124435 NCI NIH HHS
• P30 CA008748 NCI NIH HHS

• CRISPR/Cas9
• cancer
• disease models
• genome editing
• mouse models

RAS network activation is common in human cancers and, in acute myeloid leukemia (AML), achieved mainly through gain-of-function mutations in KRAS, NRAS, or the FLT3 receptor tyrosine kinase¹. In mice, we show that premalignant myeloid cells harboring a Kras^G12D allele retain low Ras signaling owing to a negative feedback involving Spry4 that prevents transformation. In humans, SPRY4 is located on chromosome 5q, a region affected by large heterozygous deletion that are associated with an aggressive disease in which gain-of-function RAS pathway mutations are rare. These 5q deletions often co-occur with chromosome 17 alterations involving deletion of NF1 - another RAS negative regulator - and TP53. Accordingly, combined suppression of Spry4, Nf1 and Trp53 produces high Ras signaling and drives AML in mice. Therefore, SPRY4 is a 5q tumor suppressor whose disruption contributes to a lethal AML subtype that appears to acquire RAS pathway activation through loss of negative regulators.

• CDK9
• MYC
• RNAi screen
• oncogene addiction
• transcription elongation

• Animals
• Dyneins/metabolism
• Erythroblasts/cytology
• Erythroblasts/metabolism
• Erythropoiesis
• Mice
• Protein Binding
• Reticulocytes/cytology
• Reticulocytes/metabolism
• Tripartite Motif Proteins
• Ubiquitin-Protein Ligases/genetics
• Ubiquitin-Protein Ligases/metabolism
• Ubiquitination

• U01 HL099656 NHLBI NIH HHS
• P30 DK090969 NIDDK NIH HHS
• F30 DK102291 NIDDK NIH HHS
• R56 DK061692 NIDDK NIH HHS
• T32 GM007170 NIGMS NIH HHS
• T32 GM008216 NIGMS NIH HHS
• R01 DK061692 NIDDK NIH HHS
• R01 GM048661 NIGMS NIH HHS
• U01 HL099993 NHLBI NIH HHS
• P01 HL110860 NHLBI NIH HHS
• DK61692 NIDDK NIH HHS
• GM007170 NIGMS NIH HHS
• T32 HL007439 NHLBI NIH HHS
• HL007439 NHLBI NIH HHS
• P01 HL064190 NHLBI NIH HHS
• P30DK090969 NIDDK NIH HHS

• Cancer
• RNAi
• Treatment

• Alleles
• Cell Line, Tumor
• Flow Cytometry
• Gene Expression/radiation effects
• Gene Library
• HL-60 Cells
• Human Umbilical Vein Endothelial Cells
• Humans
• Normal Distribution
• RNA Interference
• RNA, Messenger/metabolism
• RNA, Small Interfering/genetics
• RNA, Small Interfering/metabolism
• Radiation, Ionizing
• Sequence Analysis, DNA
• Tumor Suppressor Protein p53/antagonists & inhibitors
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• Bnip3
• HIF1
• hypoxia
• melanoma
• miRNA

• Animals
• Carcinoma, Pancreatic Ductal/metabolism
• Carcinoma, Pancreatic Ductal/pathology
• Disease Models, Animal
• Gene Expression Profiling
• Humans
• Mice
• Neoplasm Metastasis
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Receptor, Platelet-Derived Growth Factor beta/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• CA 013106 NCI NIH HHS
• P30 CA008748 NCI NIH HHS
• P01 CA087497 NCI NIH HHS
• P01 CA013106 NCI NIH HHS
• 17263 Cancer Research UK
• P01 CA129243 NCI NIH HHS

Saborowski et al. developed a flexible embryonic stem cell (ESC)-based mouse model for pancreatic cancer. The ESCs harbor a latent Kras mutant, a homing cassette, and other genetic elements needed for rapid insertion and conditional expression of tetracycline-controlled transgenes, including fluorescence-coupled shRNAs. This model produces a disease that follows the progression of human pancreatic cancer, and they used it to dissect temporal roles for Pten and c-Myc in pancreatic cancer development and maintenance.

Genetically engineered mouse models (GEMMs) have greatly expanded our knowledge of pancreatic ductal adenocarcinoma (PDAC) and serve as a critical tool to identify and evaluate new treatment strategies. However, the cost and time required to generate conventional pancreatic cancer GEMMs limits their use for investigating novel genetic interactions in tumor development and maintenance. To address this problem, we developed flexible embryonic stem cell (ESC)-based GEMMs that facilitate the rapid generation of genetically defined multiallelic chimeric mice without further strain intercrossing. The ESCs harbor a latent Kras mutant (a nearly ubiquitous feature of pancreatic cancer), a homing cassette, and other genetic elements needed for rapid insertion and conditional expression of tetracycline-controlled transgenes, including fluorescence-coupled shRNAs capable of efficiently silencing gene function by RNAi. This system produces a disease that recapitulates the progression of pancreatic cancer in human patients and enables the study and visualization of the impact of gene perturbation at any stage of pancreas cancer progression. We describe the use of this approach to dissect temporal roles for the tumor suppressor Pten and the oncogene c-Myc in pancreatic cancer development and maintenance.

• RMCE
• embryonic stem cell
• kras
• mouse model
• pancreas
• pancreatic cancer

Inhibition of gene expression through siRNAs is a tool increasingly used for the study of gene function in model systems, including transgenic mice. To achieve perdurable effects, the stable expression of siRNAs by an integrated transgenic construct is necessary. For transgenic siRNA expression, promoters transcribed by either RNApol II or III (such as U6 or H1 promoters) can be used. Relatively large amounts of small RNAs synthesis are achieved when using RNApol III promoters, which can be advantageous in knockdown experiments. To study the feasibility of H1 promoter-driven RNAi-expressing constructs for protein knockdown in transgenic mice, we chose IKK1 as the target gene. Our results indicate that constructs containing the H1 promoter are sensitive to the presence of prokaryotic sequences and to transgene position effects, similar to RNApol II promoters-driven constructs. We observed variable expression levels of transgenic siRNA among different tissues and animals and a reduction of up to 80% in IKK1 expression. Furthermore, IKK1 knockdown led to hair follicle alterations. In summary, we show that constructs directed by the H1 promoter can be used for knockdown of genes of interest in different organs and for the generation of animal models complementary to knockout and overexpression models.

• Animals
• Cell Line
• Cerebellum/metabolism
• Down-Regulation
• Embryonic Stem Cells/metabolism
• Gene Expression
• Gene Expression Regulation
• Gene Order
• Gene Silencing
• Gene Targeting
• Mice
• Mice, Transgenic
• Multigene Family
• Precursor Cells, B-Lymphoid/metabolism
• RNA Interference
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Transgenes

mir-17-92, a potent polycistronic oncomir, encodes six mature miRNAs with complex modes of interactions. In the Eμ-myc Burkitt’s lymphoma model, mir-17-92 exhibits potent oncogenic activity by repressing c-Myc-induced apoptosis, primarily through its miR-19 components. Surprisingly, mir-17-92 also encodes the miR-92 component that negatively regulates its oncogenic cooperation with c-Myc. This miR-92 effect is, at least in part, mediated by its direct repression of Fbw7, which promotes the proteosomal degradation of c-Myc. Thus, overexpressing miR-92 leads to aberrant c-Myc increase, imposing a strong coupling between excessive proliferation and p53-dependent apoptosis. Interestingly, miR-92 antagonizes the oncogenic miR-19 miRNAs; and such functional interaction coordinates proliferation and apoptosis during c-Myc-induced oncogenesis. This miR-19:miR-92 antagonism is disrupted in B-lymphoma cells that favor a greater increase of miR-19 over miR-92. Altogether, we suggest a new paradigm whereby the unique gene structure of a polycistronic oncomir confers an intricate balance between oncogene and tumor suppressor crosstalk.

DOI:http://dx.doi.org/10.7554/eLife.00822.001

The role of genes, in very simple terms, is to be transcribed into messenger RNA molecules, which are then translated into strings of amino acids that fold into proteins. Each of these steps is extremely complex, and a wide range of other molecules can speed up, slow down, stop or otherwise disrupt the expression of genes as protein products. Genes can also code for nucleic acids that are not translated into proteins, such as microRNAs. These are small RNA molecules that can reduce the production of proteins by repressing the translation step and/or by partially degrading the messenger RNA molecules.

mir-17-92 is a gene that exemplifies much of this complexity. It codes for six different microRNAs in a single primary transcript, and has been implicated in a number of cancers, including lung cancer, Burkitt’s lymphoma and other forms of lymphomas and leukemia. One of six microRNAs has a longer evolutionary history than the remaining five: mir-92 is found in vertebrates, chordates and invertebrates, whereas the other five are only found in vertebrates. However, it is not known how or why the mir-17-92 gene evolved to code for multiple different microRNAs.

Olive et al. have studied how these mir-17-92 microRNAs functionally interact in mice with Burkitt’s lymphoma, a form of cancer that is associated with a gene called c-Myc being over-activated. Mutations in this gene promote the proliferation of cells, and in cooperation with other genetic lesions, this ultimately leads to cancer. mir-17-92 is implicated in this cancer because it represses the process of programmed cell death (which is induced by the protein c-Myc) that the body employs to stop tumors growing.

Olive et al. found that deleting one of the six microRNAs, miR-92, increased the tendency of the mir-17-92 gene to promote Burkitt’s lymphoma. By repressing an enzyme called Fbw7, miR-92 causes high levels of c-Myc to be produced. While this leads to the uncontrolled proliferation of cells that promotes cancer, it also increases programmed cell death, at least in part, by activating the p53 pathway, a well-known tumor suppression pathway. The experiments also revealed that the action of miR-92 and that of one of the other microRNAs, miR-19, were often opposed to each other. These findings have revealed an unexpected interaction among different components within a single microRNA gene, which acts to maintain an intricate balance between pathways that promote and suppress cancer.

DOI:http://dx.doi.org/10.7554/eLife.00822.002

• Eμ-myc lymphoma
• Mouse
• apoptosis
• c-Myc
• microRNAs
• p53

• autophagy
• mitochondria
• mitophagy
• p14ARF
• p19ARF

• Animals
• Autophagy/genetics
• Autophagy/physiology
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p16/genetics
• Cyclin-Dependent Kinase Inhibitor p16/metabolism
• Humans
• Mice
• Mitochondria/metabolism
• Mutation/genetics
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Proteins/genetics

• R01 CA102184 NCI NIH HHS
• R01 CA139319 NCI NIH HHS
• T32 CA009035 NCI NIH HHS
• P30 CA10815 NCI NIH HHS

• Computational modeling
• RNAi
• Regulatory networks
• Signaling pathways