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Disease Models & Mechanisms Sep 2014In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the... (Review)
Review
In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Despite the inefficiency of ATP generation through glycolysis, the breakdown of glucose into lactate provides cancer cells with a number of advantages, including the ability to withstand fluctuations in oxygen levels, and the production of intermediates that serve as building blocks to support rapid proliferation. Recent evidence from many cancer types supports the notion that pervasive metabolic reprogramming in cancer and stromal cells is a crucial feature of neoplastic transformation. Two key transcription factors that play major roles in this metabolic reprogramming are hypoxia inducible factor-1 (HIF1) and MYC. Sirtuin-family deacetylases regulate diverse biological processes, including many aspects of tumor biology. Recently, the sirtuin SIRT6 has been shown to inhibit the transcriptional output of both HIF1 and MYC, and to function as a tumor suppressor. In this Review, we highlight the importance of HIF1 and MYC in regulating tumor metabolism and their regulation by sirtuins, with a main focus on SIRT6.
Topics: Cell Proliferation; Genes, myc; Humans; Hypoxia-Inducible Factor 1; Neoplasms; Proto-Oncogene Proteins c-myc; Sirtuins
PubMed: 25085992
DOI: 10.1242/dmm.016287 -
Biomedicine & Pharmacotherapy =... Jun 2023Ubiquitin-specific protease 7 (USP7) is one of the deubiquitinating enzymes (DUBs) that remove mono or polyubiquitin chains from target proteins. Depending on cancer...
Ubiquitin-specific protease 7 (USP7) is one of the deubiquitinating enzymes (DUBs) that remove mono or polyubiquitin chains from target proteins. Depending on cancer types, USP7 has two opposing roles: oncogene or tumor suppressor. Moreover, it also known that USP7 functions in the cell cycle, apoptosis, DNA repair, chromatin remodeling, and epigenetic regulation through deubiquitination of several substrates including p53, mouse double minute 2 homolog (MDM2), Myc, and phosphatase and tensin homolog (PTEN). The [P/A/E]-X-X-S and K-X-X-X-K motifs of target proteins are necessary elements for the binding of USP7. In a previous study, we identified a novel substrate of USP7 through bioinformatics analysis using the binding motifs for USP7, and suggested that it can be an effective tool for finding new substrates for USP7. In the current study, gene ontology (GO) analysis revealed that putative target proteins having the [P/A/E]-X-X-S and K-X-X-K motifs are involved in transcriptional regulation. Moreover, through protein-protein interaction (PPI) analysis, we discovered that USP7 binds to the AVMS motif of ETS proto-oncogene 2 (ETS2) and deubiquitinates M1-, K11-, K27-, and K29-linked polyubiquitination of ETS2. Furthermore, we determined that suppression of USP7 decreases the protein stability of ETS2 and inhibits the transcriptional activity of ETS2 by disrupting the binding between the GGAA/T core motif and ETS2. Therefore, we propose that USP7 can be a novel target in cancers related to the dysregulation of ETS2.
Topics: Epigenesis, Genetic; Proto-Oncogenes; Tumor Suppressor Protein p53; Ubiquitin Thiolesterase; Ubiquitin-Specific Peptidase 7; Humans; Proto-Oncogene Protein c-ets-2
PubMed: 37062218
DOI: 10.1016/j.biopha.2023.114700 -
Scientific Reports Jul 2020The extent to which mammalian cells share similar transcriptomes remains unclear. Notwithstanding, such cross-species gene expression inquiries have been scarce for...
The extent to which mammalian cells share similar transcriptomes remains unclear. Notwithstanding, such cross-species gene expression inquiries have been scarce for defined cell types and most lack the dissection of gene regulatory landscapes. Therefore, the work was aimed to determine C-MYC relative expression across mammalian fibroblasts (Ovis aries and Bos taurus) via cross-species RT-qPCR and comprehensively explore its regulatory landscape by in silico tools. The prediction of transcription factor binding sites in C-MYC and its 2.5 kb upstream sequence revealed substantial variation, thus indicating evolutionary-driven re-wiring of cis-regulatory elements. C-MYC and its downstream target TBX3 were up-regulated in Bos taurus fibroblasts. The relative expression of C-MYC regulators [RONIN (also known as THAP11), RXRβ, and TCF3] and the C-MYC-associated transcript elongation factor CDK9 did not differ between species. Additional in silico analyses suggested Bos taurus-specific C-MYC exonization, alternative splicing, and binding sites for non-coding RNAs. C-MYC protein orthologs were highly conserved, while variation was in the transactivation domain and the leucine zipper motif. Altogether, mammalian fibroblasts display evolutionary-driven C-MYC relative expression that should be instructive for understanding cellular physiology, cellular reprogramming, and C-MYC-related diseases.
Topics: Amino Acid Sequence; Animals; Cattle; Cyclin-Dependent Kinase 9; Evolution, Molecular; Fibroblasts; Gene Expression; Genes, myc; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-myc; Regulatory Elements, Transcriptional; Sequence Homology, Amino Acid; Sheep, Domestic; Species Specificity; T-Box Domain Proteins; Transcriptome
PubMed: 32632086
DOI: 10.1038/s41598-020-67391-x -
Life Sciences Mar 2024RBM10 is a well-known RNA binding protein that regulates alternative splicing in various disease states. We have shown a splicing-independent function of RBM10 that...
AIMS
RBM10 is a well-known RNA binding protein that regulates alternative splicing in various disease states. We have shown a splicing-independent function of RBM10 that regulates heart failure. This study aims to unravel a new biological function of RBM10 phosphorylation by proto-oncogene cSrc that enables anti-hypertrophy gene program and controls cardiac hypertrophy.
MATERIALS AND METHODS
We employ in vitro and in vivo approaches to characterise RBM10 phosphorylation at three-tyrosine residues (Y81, Y500, and Y971) by cSrc and target mRNA regulation. We also use isoproterenol induced rat heart and cellular hypertrophy model to determine role of cSrc-mediated RBM10 phosphorylation.
KEY FINDINGS
We show that RBM10 phosphorylation is induced in cellular and animal heart model of cardiac hypertrophy and regulates target mRNA expression and 3'-end formation. Inhibition of cSrc kinase or mutation of the three-tyrosine phosphorylation sites to phenylalanine accentuates myocyte hypertrophy, and results in advancement and an early attainment of hypertrophy in the heart. RBM10 is down regulated in the hypertrophic myocyte and that its re-expression reverses cellular and molecular changes in the myocyte. However, in the absence of phosphorylation (cSrc inhibition or phospho-deficient mutation), restoration of endogenous RBM10 level in the hypertrophic heart or ectopic re-expression in vitro failed to reverse cardiomyocyte hypertrophy. Mechanistically, loss of RBM10 phosphorylation inhibits nuclear localisation and interaction with Star-PAP compromising anti-hypertrophy gene expression.
SIGNIFICANCE
Our study establishes that cSrc-mediated RBM10 phosphorylation arbitrates anti-hypertrophy gene program. We also report a new functional regulation of RBM10 by phosphorylation that is poised to control heart failure.
Topics: Rats; Animals; Phosphorylation; Cardiomegaly; Heart Failure; Proto-Oncogenes; RNA, Messenger; Tyrosine; Myocytes, Cardiac
PubMed: 38309577
DOI: 10.1016/j.lfs.2024.122482 -
Cells Apr 2023The proto-oncogene has been intensively studied primarily in vertebrate cell culture systems. Myc transcription factors control fundamental cellular processes such as...
The proto-oncogene has been intensively studied primarily in vertebrate cell culture systems. Myc transcription factors control fundamental cellular processes such as cell proliferation, cell cycle control and stem cell maintenance. Myc interacts with the Max protein and Myc/Max heterodimers regulate thousands of target genes. The genome of the freshwater polyp encodes four genes (). Previous structural and biochemical characterization showed that the Myc1 and Myc2 proteins share high similarities with vertebrate c-Myc, and their expression patterns suggested a function in adult stem cell maintenance. In contrast, an additional Myc protein termed Myc3 is highly divergent, lacking the common N-terminal domain and all conserved Myc-boxes. Single cell transcriptome analysis revealed that the gene is expressed in a distinct population of interstitial precursor cells committed to nerve- and gland-cell differentiation, where the Myc3 protein may counteract the stemness actions of Myc1 and Myc2 and thereby allow the implementation of a differentiation program. In vitro DNA binding studies showed that Myc3 dimerizes with Max, and this dimer efficiently binds to DNA containing the canonical Myc consensus motif (E-box). In vivo cell transformation assays in avian fibroblast cultures further revealed an unexpected high potential for oncogenic transformation in the conserved Myc3 C-terminus, as compared to Myc2 or Myc1. Structure modeling of the Myc3 protein predicted conserved amino acid residues in its bHLH-LZ domain engaged in Myc3/Max dimerization. Mutating these amino acid residues in the human c-Myc (MYC) sequence resulted in a significant decrease in its cell transformation potential. We discuss our findings in the context of oncogenic transformation and cell differentiation, both relevant for human cancer, where Myc represents a major driver.
Topics: Animals; Humans; Hydra; Amino Acid Sequence; Genes, myc; Helix-Loop-Helix Motifs; Amino Acids
PubMed: 37174665
DOI: 10.3390/cells12091265 -
Medical Principles and Practice :... 2016Cellular blebbing is a unique form of dynamic protrusion emanating from the plasma membrane which can be either apoptotic or nonapoptotic in nature. Blebs have been... (Review)
Review
Cellular blebbing is a unique form of dynamic protrusion emanating from the plasma membrane which can be either apoptotic or nonapoptotic in nature. Blebs have been observed in a wide variety of cell types and in response to multiple mechanical and chemical stimuli. They have been linked to various physiological and pathological processes including tumor motility and invasion, as well as to various immunological disorders. They can form and retract extremely rapidly in seconds or minutes, or slowly over hours or days. This review focuses on recent evidence regarding the role of blebbing in cell locomotion with particular emphasis on its role in tumor metastasis, indicating the role of specific causative molecules. The phenomenon of blebbing has been observed in endocrine-resistant breast cancer cells in response to brief exposure to extracellular alkaline pH, which leads to enhanced invasive capacity. Genetic or pharmacological targeting of cellular blebs could serve as a potential therapeutic option to control tumor metastasis.
Topics: Animals; Apoptosis; Blister; Breast Neoplasms; Cell Membrane; Cell Movement; Death-Associated Protein Kinases; Female; Humans; Immune System Diseases; Neoplasm Metastasis; Proto-Oncogenes; rhoA GTP-Binding Protein; src-Family Kinases
PubMed: 26488882
DOI: 10.1159/000441848 -
Molecular Cancer Jan 2024In the early 1990's a group of unrelated genes were identified from the sites of recurring translocations in B-cell lymphomas. Despite sharing the nomenclature 'Bcl',... (Review)
Review
In the early 1990's a group of unrelated genes were identified from the sites of recurring translocations in B-cell lymphomas. Despite sharing the nomenclature 'Bcl', and an association with blood-borne cancer, these genes have unrelated functions. Of these genes, BCL2 is best known as a key cancer target involved in the regulation of caspases and other cell viability mechanisms. BCL3 on the other hand was originally identified as a non-canonical regulator of NF-kB transcription factor pathways - a signaling mechanism associated with important cell outcomes including many of the hallmarks of cancer. Most of the early investigations into BCL3 function have since focused on its role in NF-kB mediated cell proliferation, inflammation/immunity and cancer. However, recent evidence is coming to light that this protein directly interacts with and modulates a number of other signaling pathways including DNA damage repair, WNT/β-catenin, AKT, TGFβ/SMAD3 and STAT3 - all of which have key roles in cancer development, metastatic progression and treatment of solid tumours. Here we review the direct evidence demonstrating BCL3's central role in a transcriptional network of signaling pathways that modulate cancer biology and treatment response in a range of solid tumour types and propose common mechanisms of action of BCL3 which may be exploited in the future to target its oncogenic effects for patient benefit.
Topics: Humans; NF-kappa B; Neoplasm Recurrence, Local; Proto-Oncogenes; Hematologic Neoplasms; Cell Proliferation
PubMed: 38195591
DOI: 10.1186/s12943-023-01922-8 -
Anticancer Research Feb 2019Endometrial cancer (EC) is the most common cancer of the female genital tract, resulting annually in 76,000 related deaths worldwide. EC originates either from... (Review)
Review
Endometrial cancer (EC) is the most common cancer of the female genital tract, resulting annually in 76,000 related deaths worldwide. EC originates either from oestrogen-related proliferative endometrium (type I, endometrioid), or from atrophic endometrium (type II, non-endometrioid). Each type of EC is characterized by different molecular profile alterations. The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a signalling protein which moderates response to various extracellular signals via down-regulation of the mitogen-activated protein kinase (MAPK) or phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT) pathways. This article reviews the role of KRAS in predicting transition from hyperplastic endometrium to early-stage well-differentiated EC, as well as further invasive proliferation of the tumour to advanced-stage disease. KRAS seems to be directly associated with type I EC, and most studies support its early involvement in carcinogenesis. Current evidence correlates KRAS mutations with increased cell proliferation and apoptosis, as well as up-regulation of endometrial cell oestrogen receptors. Tumours positive for KRAS mutation can harbour hypermethylation-related changes in genome expression, and this can be the cause of concurrent loss of DNA repair proteins. Despite some evidence that KRAS mutation status affects cancer progression, a consensus is yet to be reached. Based on the available evidence, we suggest that screening for KRAS mutations in patients with hyperplastic endometrium or early-stage type I EC, may provide important information for prognosis stratification, and further provision of personalised treatment options.
Topics: Biomarkers, Tumor; Cell Proliferation; Disease Progression; Endometrial Neoplasms; Endometrium; Estrogens; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Mutation; Neoplasm Staging; Proto-Oncogene Proteins p21(ras); Receptors, Estrogen
PubMed: 30711927
DOI: 10.21873/anticanres.13145 -
Blood May 2020
Topics: Animals; Genes, ras; Hematopoiesis; Lipoylation; Mice; Oncogenes
PubMed: 32407527
DOI: 10.1182/blood.2020005720 -
Archives of Pathology & Laboratory... Dec 2016- Inv(3)(q21q26)/t(3;3)(q21;q26.2) is the most common form of genetic abnormality of the so-called 3q21q26 syndrome. Myeloid neoplasms with 3q21q26 aberrancies include... (Review)
Review
CONTEXT
- Inv(3)(q21q26)/t(3;3)(q21;q26.2) is the most common form of genetic abnormality of the so-called 3q21q26 syndrome. Myeloid neoplasms with 3q21q26 aberrancies include acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and blast crisis of myeloproliferative neoplasms. Recent advances on myeloid neoplasms with inv(3)/t(3;3) with regard to clinicopathologic features and novel molecular or genomic findings warrant a comprehensive review on this topic.
OBJECTIVE
- To review the clinicopathologic features and molecular as well as genomic alterations in myeloid neoplasms with inv(3)/t(3;3).
DATA SOURCES
- The data came from published articles in English-language literature.
CONCLUSIONS
- At the clinicopathologic front, recent studies on MDS with inv(3)/t(3;3) have highlighted their overlapping clinicopathologic features with and similar overall survival to that of inv(3)/t(3;3)-harboring AML regardless of the percentage of myeloid blasts. On the molecular front, AML and MDS with inv(3)/t(3;3) exhibit gene mutations, which affect the RAS/receptor tyrosine kinase pathway. Furthermore, functional genomic studies using genomic editing and genome engineering have shown that the reallocation of the GATA2 distal hematopoietic enhancer to the proximity of the promoter of ectopic virus integration site 1 (EVI1) without the formation of a new oncogenic fusion transcript is the molecular mechanism underlying these inv(3)/t(3;3) myeloid neoplasms. Although the AML and MDS with inv(3)/t(3;3) are listed as a separate category of myeloid malignancies in the 2008 World Health Organization classification, the overlapping clinicopathologic features, similar overall survival, and identical patterns at the molecular and genomic levels between AML and MDS patients with inv(3)/t(3;3) may collectively favor a unification of AML and MDS with inv(3)/t(3;3) as AML or myeloid neoplasms with inv(3)/t(3;3) regardless of the blast count.
Topics: Animals; Blast Crisis; Chromosome Inversion; Chromosomes, Human, Pair 3; DNA-Binding Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; MDS1 and EVI1 Complex Locus Protein; Male; Molecular Diagnostic Techniques; Myelodysplastic Syndromes; Myeloproliferative Disorders; Oncogene Proteins, Fusion; Pathology, Clinical; Prognosis; Protein Domains; Proto-Oncogenes; Transcription Factors; Translocation, Genetic
PubMed: 27628325
DOI: 10.5858/arpa.2016-0059-RA