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The Journal of Biological Chemistry Oct 2022Family with sequence similarity 83 A (FAM83A) is a newly discovered proto-oncogene that has been shown to play key roles in various cancers. However, the function of...
Family with sequence similarity 83 A (FAM83A) is a newly discovered proto-oncogene that has been shown to play key roles in various cancers. However, the function of FAM83A in other physiological processes is not well known. Here, we report a novel function of FAM83A in adipocyte differentiation. We used an adipocyte-targeting fusion oligopeptide (FITC-ATS-9R) to deliver a FAM83A-sgRNA/Cas9 plasmid to knockdown Fam83a (ATS/sg-FAM83A) in white adipose tissue in mice, which resulted in reduced white adipose tissue mass, smaller adipocytes, and mitochondrial damage that was aggravated by a high-fat diet. In cultured 3T3-L1 adipocytes, we found loss or knockdown of Fam83a significantly repressed lipid droplet formation and downregulated the expression of lipogenic genes and proteins. Furthermore, inhibition of Fam83a decreased mitochondrial ATP production through blockage of the electron transport chain, associated with enhanced apoptosis. Mechanistically, we demonstrate FAM83A interacts with casein kinase 1 (CK1) and promotes the permeability of the mitochondrial outer membrane. Furthermore, loss of Fam83a in adipocytes hampered the formation of the TOM40 complex and impeded CK1-driven lipogenesis. Taken together, these results establish FAM83A as a critical regulator of mitochondria maintenance during adipogenesis.
Topics: Animals; Mice; 3T3-L1 Cells; Adipocytes, White; Adipogenesis; Casein Kinase I; Cell Differentiation; Mitochondria; Proto-Oncogenes; Neoplasm Proteins
PubMed: 35931121
DOI: 10.1016/j.jbc.2022.102339 -
Seminars in Hematology Apr 2015MYC is a transcription factor associated with numerous physiological functions, including apoptosis, and strong oncogenic potential. MYC expression is tightly regulated... (Review)
Review
MYC is a transcription factor associated with numerous physiological functions, including apoptosis, and strong oncogenic potential. MYC expression is tightly regulated in normal lymphoid cells with high levels in the initial steps of the secondary lymphoid follicle formation and in a subset of centrocytes of the germinal center light zone. BCL6 and BLIMP1 repress MYC expression in normal germinal center B and plasma cells, respectively. Paradoxically, most lymphomas with MYC genetic alterations originate from cells that usually do not express MYC, suggesting that these tumors need to develop additional oncogenic events to overcome the MYC regulatory mechanisms and also its proapoptotic function. MYC rearrangements, and to a lesser extent gene amplifications, have been detected in approximately 5% to 14% of diffuse large B-cell lymphoma (DLBCL) and these alterations are frequently associated with BCL2 or BCL6 rearrangements. The concurrent presence of these alterations confers a more aggressive behavior to the tumors with poor outcome of the patients. BCL2 and MYC protein may also be coexpressed in DLBCL independently of gene alterations and this double expression also confers poor prognosis, although not as dismal as that of double genetic hits. Additional factors may modulate the biological effect of the double hit lesions because tumors in which MYC is translocated to non-IGH partner or MYC and BCL2 protein that are expressed at lower levels may have a less aggressive behavior. Further studies are needed to define the clinical implications of MYC aberrations in DLBCL and determine the most appropriate diagnostic strategy to identify these tumors.
Topics: Animals; DNA-Binding Proteins; Genes, myc; Humans; Lymphoma, Large B-Cell, Diffuse; Mutation; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-6; Translocation, Genetic
PubMed: 25805589
DOI: 10.1053/j.seminhematol.2015.01.009 -
Trends in Cancer Dec 2021Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point... (Review)
Review
Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Proto-Oncogenes
PubMed: 34391699
DOI: 10.1016/j.trecan.2021.07.003 -
British Journal of Haematology Mar 2015Double hit lymphomas (DHL) represent a subset of highly aggressive B-cell malignancies characterized by the presence of recurrent cytogenetic rearrangements affecting... (Review)
Review
Double hit lymphomas (DHL) represent a subset of highly aggressive B-cell malignancies characterized by the presence of recurrent cytogenetic rearrangements affecting MYC and either BCL2 and/or BCL6. Recent studies have expanded the concept to include MYC/BCL2 protein co-expressing lymphomas. Around 5-10% of diffuse large B-cell lymphomas are 'double hit' using the cytogenetic definition, whilst around 30-40% are MYC/BCL2 protein co-expressing. In this review, we provide a comprehensive overview of this condition written with the practicing clinician in mind, covering the definition and classification, when DHL should be suspected and how to make the diagnosis, the prognostic factors and a detailed discussion of recent evidence regarding optimal therapy. In particular, we discuss choice of induction regimen, the role of central nervous system-directed prophylaxis, stem cell transplantation and relapsing or refractory disease and provide our opinions based on the currently available evidence. Finally, we highlight some of the more exciting therapies currently in development for this highly aggressive disease.
Topics: Antineoplastic Combined Chemotherapy Protocols; Gene Rearrangement, B-Lymphocyte; Genes, bcl-2; Genes, myc; Humans; Lymphoma, B-Cell; Prognosis; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc
PubMed: 25529575
DOI: 10.1111/bjh.13276 -
Nature Communications Feb 2024The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively...
The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYC but not MYC cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYC murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.
Topics: Humans; Mice; Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Proto-Oncogene Proteins c-myc; Genes, myc; Cell Transformation, Neoplastic; Carcinogenesis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38302473
DOI: 10.1038/s41467-024-45128-y -
Journal of Hematology & Oncology Aug 2021MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and... (Review)
Review
MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; DNA Damage; Drug Discovery; Gene Expression Regulation, Neoplastic; Genes, myc; Hematologic Neoplasms; Humans; Models, Molecular; Prognosis; Proto-Oncogene Proteins c-myc
PubMed: 34372899
DOI: 10.1186/s13045-021-01111-4 -
Cell Feb 2016Mouse embryonic stem cells (mESCs) are capable of unlimited proliferation without losing pluripotency. Scognamiglio et al. now reveal that Myc depletion shifts mESCs...
Mouse embryonic stem cells (mESCs) are capable of unlimited proliferation without losing pluripotency. Scognamiglio et al. now reveal that Myc depletion shifts mESCs into a dormant state reminiscent of embryonic diapause in which pluripotency remains fully preserved, thus decoupling pluripotency from proliferative programs.
Topics: Animals; Embryonic Stem Cells; Female; Genes, myc; Male; Proto-Oncogene Proteins c-myc
PubMed: 26871623
DOI: 10.1016/j.cell.2016.01.050 -
JPMA. the Journal of the Pakistan... Oct 2021To focus mainly on the role of proto-oncogene Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras) and tumour-suppressor gene p53 which are among the most commonly...
OBJECTIVE
To focus mainly on the role of proto-oncogene Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras) and tumour-suppressor gene p53 which are among the most commonly mutated genes in biliary tract carcinomas.
METHODS
The systematic review comprised research articles published between 2002 and 2019 on PubMed and Google Scholar databases which were searched using the terms 'TP53', 'K-Ras', 'mutation', 'biliary tract carcinoma', 'cholangiocarcinoma', and 'murine model'. Repetitions, duplicates and irrelevant articles were excluded. No data was retrieved from posters, presentations and symposiums, and experiments involving bile aspirations were also excluded.
RESULTS
Of the 72 articles reviewed, 11(15.3%) were included. Of them, 3(27.3%) studies, conducted in China, Japan and Taiwan, reported a positive correlation between K-Ras mutation and biliary tract carcinoma. Only 1(9%) study, conducted in China, showed the sole correlation between p53 inactivation and biliary tract carcinoma. Also, 4(36.4%) studies, conducted in China, Japan and Europe, showed a positive association of both K-Ras mutation and p53 inactivation with biliary tract carcinoma.
CONCLUSIONS
K-Ras and p53 mutation both contribute to biliary tract carcinoma. K-Ras mutation, however, has a much higher frequency compared to p53 inactivation in such cancers.
Topics: Animals; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Genes, ras; Mice; Mutation; Polymerase Chain Reaction; Tumor Suppressor Protein p53
PubMed: 34974575
DOI: 10.47391/JPMA.11-1322 -
Life Science Alliance Nov 2023Loss of c-JUN leads to early mouse embryonic death, possibly because of a failure to develop a normal cardiac system. How c-JUN regulates human cardiomyocyte cell fate...
Loss of c-JUN leads to early mouse embryonic death, possibly because of a failure to develop a normal cardiac system. How c-JUN regulates human cardiomyocyte cell fate remains unknown. Here, we used the in vitro differentiation of human pluripotent stem cells into cardiomyocytes to study the role of c-JUN. Surprisingly, the knockout of c-JUN improved cardiomyocyte generation, as determined by the number of TNNT2+ cells. ATAC-seq data showed that the c-JUN defect led to increased chromatin accessibility on critical regulatory elements related to cardiomyocyte development. ChIP-seq data showed that the knockout c-JUN increased RBBP5 and SETD1B expression, leading to improved H3K4me3 deposition on key genes that regulate cardiogenesis. The c-JUN KO phenotype could be copied using the histone demethylase inhibitor CPI-455, which also up-regulated H3K4me3 levels and increased cardiomyocyte generation. Single-cell RNA-seq data defined three cell branches, and knockout c-JUN activated more regulons that are related to cardiogenesis. In summary, our data demonstrated that c-JUN could regulate cardiomyocyte cell fate by modulating H3K4me3 modification and chromatin accessibility and shed light on how c-JUN regulates heart development in humans.
Topics: Animals; Humans; Mice; Cell Differentiation; Chromatin; Genes, jun; Human Embryonic Stem Cells; Myocytes, Cardiac; Proto-Oncogene Proteins c-jun
PubMed: 37604584
DOI: 10.26508/lsa.202302121 -
Pathology, Research and Practice Aug 2023Cancer genes are largely categorized into tumor suppressor gene (TSG) and proto-oncogene, but many have dual activities depending on the cellular context. In the present...
Cancer genes are largely categorized into tumor suppressor gene (TSG) and proto-oncogene, but many have dual activities depending on the cellular context. In the present study, we analyzed DYRK1B, ESRP1, MTSS1, ADAMTS1, and INPP5F genes known to possess the dual activities in sporadic colon cancers (CCs). By the mutation analysis, we identified DYRK1B, ESRP1, MTSS1, ADAMTS1, and INPP5F frameshift mutations in 2, 2, 3, 3, and 1 CCs in instability-high (MSI-H) cases (1.1-3.2% of MSI-H CCs), respectively, but not microsatellite stable (MSS) cases. One CC showed regional heterogeneous mutations (RHM) of ESRP1 mutation. Immunohistochemistry identified protein expression of ESRP1, MTSS1, and ADAMTS1 in the CCs, revealing that approximately 30% of CCs lost the protein expression irrespective of the MSI status. Our study showed that dual TSG and proto-oncogene genes DYRK1B, ESRP1, MTSS1, ADAMTS1, and INPP5F harbored low incidences of inactivating mutations, but that the protein losses were frequent in CCs. Our study suggests a possibility that the dual-function genes could be altered mainly at the expression level, which might contribute to CC pathogenesis.
Topics: Humans; Colorectal Neoplasms; Genes, Tumor Suppressor; Mutation; Frameshift Mutation; Colonic Neoplasms; Microsatellite Instability; Proto-Oncogenes; Microsatellite Repeats; Microfilament Proteins; Neoplasm Proteins
PubMed: 37429176
DOI: 10.1016/j.prp.2023.154659