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Journal of Hematology & Oncology Nov 2014While microRNAs (miRNAs) and the KRAS oncogene are known to be dysregulated in various cancers, little is known about the role of miRNAs in the regulation of KRAS in... (Review)
Review
While microRNAs (miRNAs) and the KRAS oncogene are known to be dysregulated in various cancers, little is known about the role of miRNAs in the regulation of KRAS in cancer. Here we review a selection of studies published in 2014 that have contributed to our understanding of the molecular mechanisms of KRAS regulation by miRNAs and the clinical relevance of sequence variants that may interfere with functional miRNA-mediated KRAS regulation.
Topics: Animals; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; MicroRNAs; Neoplasms; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins
PubMed: 25433809
DOI: 10.1186/s13045-014-0084-2 -
Biochemical Society Transactions Oct 2018Oncogenic mutations in genes underlie the pathogenesis of many human tumours, and there has been intense effort for over 30 years to develop effective and tolerated... (Review)
Review
Oncogenic mutations in genes underlie the pathogenesis of many human tumours, and there has been intense effort for over 30 years to develop effective and tolerated targeted therapeutics for patients with Ras-driven cancers. This review summarises the progress made in Ras drug discovery, highlighting some of the recent developments in directly targeting Ras through advances in small molecule drug design and novel therapeutic strategies.
Topics: Animals; Antineoplastic Agents; Drug Design; Drug Discovery; Genes, ras; Humans; Mice; Molecular Targeted Therapy; Mutation; Neoplasms; Oligonucleotides, Antisense; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); RNA, Small Interfering; Signal Transduction; ras Proteins
PubMed: 30154091
DOI: 10.1042/BST20170529 -
Blood Mar 2023
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Cell Cycle; Proto-Oncogenes; Genomic Instability; Biology; Proto-Oncogene Proteins
PubMed: 36951882
DOI: 10.1182/blood.2022018435 -
Blood Cancer Journal Nov 2022Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account for a minority of lymphoproliferative neoplasms. These T-cell derived...
Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account for a minority of lymphoproliferative neoplasms. These T-cell derived neoplasms, while molecularly and genetically heterogeneous, exploit transcription factors and signaling pathways that are critically important in normal T-cell biology, including those implicated in antigen-, costimulatory-, and cytokine-receptor signaling. The transcription factor GATA-3 regulates the growth and proliferation of both immature and mature T cells and has recently been implicated in T-cell neoplasms, including the most common mature T-cell lymphoma observed in much of the Western world. Here we show that GATA-3 is a proto-oncogene across the spectrum of T-cell neoplasms, including those derived from T-cell progenitors and their mature progeny, and further define the transcriptional programs that are GATA-3 dependent, which include therapeutically targetable gene products. The discovery that p300-dependent acetylation regulates GATA-3 mediated transcription by attenuating DNA binding has novel therapeutic implications. As most patients afflicted with GATA-3 driven T-cell neoplasms will succumb to their disease within a few years of diagnosis, these findings suggest opportunities to improve outcomes for these patients.
Topics: Humans; Cell Differentiation; DNA-Binding Proteins; Neoplasms; Proto-Oncogenes; T-Lymphocyte Subsets; Leukemia, Lymphoid
PubMed: 36329027
DOI: 10.1038/s41408-022-00745-y -
JCI Insight Jun 2023Cyclic GMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an antitumor immune response. Recent studies reveal that cGAS is frequently inhibited in...
Cyclic GMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an antitumor immune response. Recent studies reveal that cGAS is frequently inhibited in cancer, and therapeutic targets to promote antitumor cGAS function remain elusive. SRC is a proto-oncogene tyrosine kinase and is expressed at elevated levels in numerous cancers. Here, we demonstrate that SRC expression in primary and metastatic bladder cancer negatively correlates with innate immune gene expression and immune cell infiltration. We determine that SRC restricts cGAS signaling in human cell lines through SRC small molecule inhibitors, depletion, and overexpression. cGAS and SRC interact in cells and in vitro, while SRC directly inhibits cGAS enzymatic activity and DNA binding in a kinase-dependent manner. SRC phosphorylates cGAS, and inhibition of cGAS Y248 phosphorylation partially reduces SRC inhibition. Collectively, our study demonstrates that cGAS antitumor signaling is hindered by the proto-oncogene SRC and describes how cancer-associated proteins can regulate the innate immune system.
Topics: Humans; Nucleotidyltransferases; Immunity, Innate; Neoplasms; DNA; Proto-Oncogenes
PubMed: 37166992
DOI: 10.1172/jci.insight.167270 -
Methods in Molecular Biology (Clifton,... 2021The MYC oncogene was originally identified as a transduced allele (v-myc) in the genome of the highly oncogenic avian retrovirus MC29. The protein product (MYC) of the...
The MYC oncogene was originally identified as a transduced allele (v-myc) in the genome of the highly oncogenic avian retrovirus MC29. The protein product (MYC) of the cellular MYC (c-myc) protooncogene represents the key component of a transcription factor network controlling the expression of a large fraction of all human genes. MYC regulates fundamental cellular processes like growth control, metabolism, proliferation, differentiation, and apoptosis. Mutational deregulation of MYC, leading to increased levels of the MYC protein, is a frequent event in the etiology of human cancers. In this chapter, we describe cell systems and experimental strategies to quantify the oncogenic potential of MYC alleles, to test MYC inhibitors, and to monitor MYC-specific protein-protein interactions that are relevant for the cell transformation process. We also describe experimental procedures to study the evolutionary origin of MYC and to analyze structure, function, and regulation of the ancestral MYC proto-oncogenes.
Topics: Alleles; Amino Acid Sequence; Animals; Carcinogenesis; Cell Transformation, Neoplastic; Evolution, Molecular; Genes, myc; Humans; Mutation; Neoplasms; Oncogenes; Protein Interaction Mapping; Proto-Oncogene Proteins c-myc; Transcription Factors
PubMed: 34019288
DOI: 10.1007/978-1-0716-1476-1_6 -
Cytokine & Growth Factor Reviews Jun 2017Upon antigen stimulation, quiescent naive T cells undergo a phase of cell mass accumulation followed by cell cycle entry, clonal expansion, differentiation into... (Review)
Review
Upon antigen stimulation, quiescent naive T cells undergo a phase of cell mass accumulation followed by cell cycle entry, clonal expansion, differentiation into functional subsets and back again to a quiescent state as they develop into memory cells. The transitions between these distinct cellular states place unique metabolic demands on energy, redox and biosynthesis. To fulfill these demands, T cells switch back and forth between their primary catabolic pathways. While quiescent naive and memory T cells largely rely on the oxidation of fatty acids and glucose, active T cells rely on glycolysis and glutaminolysis to sustain cell growth, proliferation and differentiation. Beyond several key signaling kinase cascades, the hypoxia inducible factor 1 (HIF-1) and the proto-oncogene MYC, act alone or in concert, to coordinate T cell metabolic reprogramming, cell proliferation, functional differentiation and apoptosis, enabling a robust T cell-mediated adaptive immune response.
Topics: Adaptive Immunity; Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Genes, myc; Glucose; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lymphocyte Activation; Proto-Oncogene Mas; Proto-Oncogene Proteins c-myc; Signal Transduction; T-Lymphocytes
PubMed: 28363691
DOI: 10.1016/j.cytogfr.2017.03.004 -
JCI Insight Jan 2022KRAS mutations are the drivers of various cancers, including non-small cell lung cancer, colon cancer, and pancreatic cancer. Over the last 30 years, immense efforts... (Review)
Review
KRAS mutations are the drivers of various cancers, including non-small cell lung cancer, colon cancer, and pancreatic cancer. Over the last 30 years, immense efforts have been made to inhibit KRAS mutants and oncogenic KRAS signaling using inhibitors. Recently, specific targeting of KRAS mutants with small molecules revived the hopes for successful therapies for lung, pancreatic, and colorectal cancer patients. Moreover, advances in gene editing, protein engineering, and drug delivery formulations have revolutionized cancer therapy regimens. New therapies aim to improve immune surveillance and enhance antitumor immunity by precisely targeting cancer cells harboring oncogenic KRAS. Here, we review recent KRAS-targeting strategies, their therapeutic potential, and remaining challenges to overcome. We also highlight the potential synergistic effects of various combinatorial therapies in preclinical and clinical trials.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Genes, ras; Humans; Mice; Mutation; Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 35014625
DOI: 10.1172/jci.insight.153688 -
The EMBO Journal Dec 2017Transcription factors of the MYC family are deregulated in the majority of all human cancers. Oncogenic levels of MYC reprogram cellular metabolism, a hallmark of cancer... (Review)
Review
Transcription factors of the MYC family are deregulated in the majority of all human cancers. Oncogenic levels of MYC reprogram cellular metabolism, a hallmark of cancer development, to sustain the high rate of proliferation of cancer cells. Conversely, cells need to modulate MYC function according to the availability of nutrients, in order to avoid a metabolic collapse. Here, we review recent evidence that the multiple interactions of MYC with cell metabolism are mutual and review mechanisms that control MYC levels and function in response to metabolic stress situations. The main hypothesis we put forward is that regulation of MYC levels is an integral part of the adaptation of cells to nutrient deprivation. Since such mechanisms would be particularly relevant in tumor cells, we propose that-in contrast to growth factor-dependent controls-they are not disrupted during tumorigenesis and that maintaining flexibility of expression is integral to MYC's oncogenic function.
Topics: Animals; Apoptosis; Biogenic Polyamines; Forkhead Box Protein O1; Genes, myc; Glucose; Glutamine; Humans; Mechanistic Target of Rapamycin Complex 1; Metabolic Networks and Pathways; Neoplasms; Nucleotides; Proto-Oncogene Proteins c-myc; Stress, Physiological
PubMed: 29127156
DOI: 10.15252/embj.201796438 -
Current Medicinal Chemistry 2021The aim of the present review is to discuss the potential link between RAS, BRAF and microsatellite instability (MSI) mutational patterns and chemotherapeutic agent... (Review)
Review
OBJECTIVES
The aim of the present review is to discuss the potential link between RAS, BRAF and microsatellite instability (MSI) mutational patterns and chemotherapeutic agent efficacy [Irinotecan (IRI) vs. Oxaliplatin (OXA)], and how this can potentially influence the choice of the chemotherapy backbone.
METHODS
Following a review of the research literature, all pertinent articles published in the core journals were selected for the study. The inclusion criteria regarded relevant clinical and pre-clinical studies on the topic of interest (Relationship of OXA and IRI to KRAS/BRAF mutations and MSI).
RESULTS
Excision repair cross complementation group 1 (ERCC1) expression is inhibited by KRAS mutation, making tumor cells more sensitive to OXA. Results from OPUS, COIN and PRIME trials support that no conclusive data are available for BRAF mutant population because of the small number of patients. Enhanced IRI cytotoxicity to MSI cell lines is due to the participation of some of the mismatch repair (MMR) components in various DNA repair processes and their role in the maintenance of the pro-apoptotic effect of IRI and G2/M cell arrest.
CONCLUSION
OXA and IRI are indispensable drugs for mCRC treatment and their selection must be as careful as that of targeted agents. We suggest taking into consideration the interaction between known genomic alterations and OXA and IRI activity to personalize chemotherapy in mCRC patients.
Topics: Colorectal Neoplasms; DNA Mismatch Repair; Genes, ras; Humans; Irinotecan; Microsatellite Instability; Mutation; Oxaliplatin; Proto-Oncogene Proteins B-raf
PubMed: 33069191
DOI: 10.2174/0929867327666201016124950