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General and Comparative Endocrinology Nov 2022Thyroid hormone (T3) is important for adult organ function and vertebrate development, particularly during the postembryonic period when many organs develop/mature into...
Thyroid hormone (T3) is important for adult organ function and vertebrate development, particularly during the postembryonic period when many organs develop/mature into their adult forms. Amphibian metamorphosis is totally dependent on T3 and can be easily manipulated, thus offering a unique opportunity for studying how T3 controls postembryonic development in vertebrates. Numerous early studies have demonstrated that T3 affects frog metamorphosis through T3 receptor (TR)-mediated regulation of T3 response genes, where TR forms a heterodimer with RXR (9-cis retinoic acid receptor) and binds to T3 response elements (TREs) in T3 response genes to regulate their expression. We have previously identified many candidate direct T3 response genes in Xenopus tropicalis tadpole intestine. Among them is the proto-oncogene Ski, which encodes a nuclear protein with complex function in regulating cell fate. We show here that Ski is upregulated in the intestine and tail of premetamorphic tadpoles upon T3 treatment and its expression peaks at stage 62, the climax of metamorphosis. We have further discovered a putative TRE in the first exon that can bind to TR/RXR in vitro and mediate T3 regulation of the promoter in vivo. These data demonstrate that Ski is activated by T3 through TR binding to a TRE in the first exon during Xenopus tropicalis metamorphosis, implicating a role of Ski in regulating cell fate during metamorphosis.
Topics: Animals; Gene Expression Regulation, Developmental; Intestines; Larva; Metamorphosis, Biological; Nuclear Proteins; Proto-Oncogenes; Receptors, Thyroid Hormone; Retinoid X Receptors; Thyroid Hormones; Triiodothyronine; Up-Regulation; Xenopus; Xenopus laevis
PubMed: 35944650
DOI: 10.1016/j.ygcen.2022.114102 -
BMC Medical Genomics Nov 2023Chronic inflammation causes bone destruction in middle ear cholesteatomas (MECs). However, the causes of their neoplastic features remain unknown. The present study...
BACKGROUND
Chronic inflammation causes bone destruction in middle ear cholesteatomas (MECs). However, the causes of their neoplastic features remain unknown. The present study demonstrated for the first time that neoplastic features of MEC are based on proto-oncogene mutations.
RESULTS
DNA was extracted from MEC and blood samples of five patients to detect somatic mutations using depth-depth exome sequencing. Exons with somatic variants were analyzed using an additional 17 MEC/blood test pairs. Variants detected in MECs but not in blood were considered pathogenic variant candidates. We analyzed the correlation between proto-oncogene (NOTCH1 and MYC) variants and the presence of bone destruction and granulation tissue formation. MYC and NOTCH1 variants were detected in two and five of the 22 samples, respectively. Two of the NOTCH1 variants were located in its specific functional domain, one was truncating and the other was a splice donor site variant. Mutations of the two genes in attic cholesteatomas (n = 14) were significantly related with bone destruction (p = 0.0148) but not with granulation tissue formation (p = 0.399).
CONCLUSIONS
This is the first study to demonstrate a relationship between neoplastic features of MEC and proto-oncogene mutations.
Topics: Humans; Cholesteatoma, Middle Ear; Ear, Middle; Mutation; Proto-Oncogenes
PubMed: 37968650
DOI: 10.1186/s12920-023-01640-6 -
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 -
Cold Spring Harbor Perspectives in... Nov 2021Lung cancer is a heterogeneous disease that is subdivided into histopathological subtypes with distinct behaviors. Each subtype is characterized by distinct features and... (Review)
Review
Lung cancer is a heterogeneous disease that is subdivided into histopathological subtypes with distinct behaviors. Each subtype is characterized by distinct features and molecular alterations that influence tumor metabolism. Alterations in tumor metabolism can be exploited by imaging modalities that use metabolite tracers for the detection and characterization of tumors. Microenvironmental factors, including nutrient and oxygen availability and the presence of stromal cells, are a critical influence on tumor metabolism. Recent technological advances facilitate the direct evaluation of metabolic alterations in patient tumors in this complex microenvironment. In addition, molecular alterations directly influence tumor cell metabolism and metabolic dependencies that influence response to therapy. Current therapeutic approaches to target tumor metabolism are currently being developed and translated into the clinic for patient therapy.
Topics: Adaptation, Physiological; Amino Acids; Blood Glucose; Genes, erbB-1; Genes, p53; Humans; Lung Neoplasms; Molecular Targeted Therapy; Nucleotides; Phenotype; Positron-Emission Tomography; Proto-Oncogene Proteins p21(ras); Tomography, X-Ray Computed; Tumor Microenvironment
PubMed: 34127512
DOI: 10.1101/cshperspect.a037838 -
Gastroenterology Jul 2023We reported that cholangiocyte senescence, regulated by the transcription factor ETS proto-oncogene 1 (ETS1), is a pathogenic feature of primary sclerosing cholangitis...
BACKGROUND & AIMS
We reported that cholangiocyte senescence, regulated by the transcription factor ETS proto-oncogene 1 (ETS1), is a pathogenic feature of primary sclerosing cholangitis (PSC). Furthermore, histone 3 lysine 27 is acetylated at senescence-associated loci. The epigenetic readers, bromodomain and extra-terminal domain (BET) proteins, bind acetylated histones, recruit transcription factors, and drive gene expression. Thus, we tested the hypothesis that BET proteins interact with ETS1 to drive gene expression and cholangiocyte senescence.
METHODS
We performed immunofluorescence for BET proteins (BRD2 and 4) in liver tissue from liver tissue from PSC patients and a mouse PSC model. Using normal human cholangiocytes (NHCs), NHCs experimentally induced to senescence (NHCsen), and PSC patient-derived cholangiocytes (PSCDCs), we assessed senescence, fibroinflammatory secretome, and apoptosis after BET inhibition or RNA interference depletion. We assessed BET interaction with ETS1 in NHCsen and tissues from PSC patient, and the effects of BET inhibitors on liver fibrosis, senescence, and inflammatory gene expression in mouse models.
RESULTS
Tissue from patients with PSC and a mouse PSC model exhibited increased cholangiocyte BRD2 and 4 protein (∼5×) compared with controls without disease. NHCsen exhibited increased BRD2 and 4 (∼2×), whereas PSCDCs exhibited increased BRD2 protein (∼2×) relative to NHC. BET inhibition in NHCsen and PSCDCs reduced senescence markers and inhibited the fibroinflammatory secretome. ETS1 interacted with BRD2 in NHCsen, and BRD2 depletion diminished NHCsen p21 expression. BET inhibitors reduced senescence, fibroinflammatory gene expression, and fibrosis in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-fed and Mdr2 mouse models.
CONCLUSION
Our data suggest that BRD2 is an essential mediator of the senescent cholangiocyte phenotype and is a potential therapeutic target for patients with PSC.
Topics: Animals; Mice; Humans; Cholangitis, Sclerosing; Liver; Gene Expression Regulation; Histones; Proto-Oncogenes; Epigenesis, Genetic
PubMed: 37059338
DOI: 10.1053/j.gastro.2023.03.235 -
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 -
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 -
Oncogene Apr 2022Oncogenic mutations in the small GTPase RAS contribute to ~30% of human cancers. In a Drosophila genetic screen, we identified novel and evolutionary conserved cancer...
Oncogenic mutations in the small GTPase RAS contribute to ~30% of human cancers. In a Drosophila genetic screen, we identified novel and evolutionary conserved cancer genes that affect Ras-driven tumorigenesis and metastasis in Drosophila including confirmation of the tetraspanin Tsp29Fb. However, it was not known whether the mammalian Tsp29Fb orthologue, TSPAN6, has any role in RAS-driven human epithelial tumors. Here we show that TSPAN6 suppressed tumor growth and metastatic dissemination of human RAS activating mutant pancreatic cancer xenografts. Whole-body knockout as well as tumor cell autonomous inactivation using floxed alleles of Tspan6 in mice enhanced Kras-driven lung tumor initiation and malignant progression. Mechanistically, TSPAN6 binds to the EGFR and blocks EGFR-induced RAS activation. Moreover, we show that inactivation of TSPAN6 induces an epithelial-to-mesenchymal transition and inhibits cell migration in vitro and in vivo. Finally, low TSPAN6 expression correlates with poor prognosis of patients with lung and pancreatic cancers with mesenchymal morphology. Our results uncover TSPAN6 as a novel tumor suppressor receptor that controls epithelial cell identify and restrains RAS-driven epithelial cancer.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; Cell Transformation, Neoplastic; Genes, ras; Humans; Mammals; Mice; Mutation; Oncogenes; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Tetraspanins
PubMed: 35184157
DOI: 10.1038/s41388-022-02223-y -
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