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Nature Biotechnology Feb 2021Tumor-specific elucidation of physical and functional oncoprotein interactions could improve tumorigenic mechanism characterization and therapeutic response prediction....
Tumor-specific elucidation of physical and functional oncoprotein interactions could improve tumorigenic mechanism characterization and therapeutic response prediction. Current interaction models and pathways, however, lack context specificity and are not oncoprotein specific. We introduce SigMaps as context-specific networks, comprising modulators, effectors and cognate binding-partners of a specific oncoprotein. SigMaps are reconstructed de novo by integrating diverse evidence sources-including protein structure, gene expression and mutational profiles-via the OncoSig machine learning framework. We first generated a KRAS-specific SigMap for lung adenocarcinoma, which recapitulated published KRAS biology, identified novel synthetic lethal proteins that were experimentally validated in three-dimensional spheroid models and established uncharacterized crosstalk with RAB/RHO. To show that OncoSig is generalizable, we first inferred SigMaps for the ten most mutated human oncoproteins and then for the full repertoire of 715 proteins in the COSMIC Cancer Gene Census. Taken together, these SigMaps show that the cell's regulatory and signaling architecture is highly tissue specific.
Topics: Algorithms; Animals; Gene Regulatory Networks; Humans; Mice; Mutation; Neoplasms; Oncogene Proteins; Organoids; Proto-Oncogene Proteins p21(ras); RNA, Small Interfering; ROC Curve; Signal Transduction
PubMed: 32929263
DOI: 10.1038/s41587-020-0652-7 -
Nature Reviews. Cancer Jul 2020Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death.... (Review)
Review
Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders. These syndromes offer an opportunity to study oncoprotein signalling and its biology in the absence of additional driver or passenger mutations, as a result of their monogenic nature. Moreover, their expression in multiple tissue lineages provides insight into the biology of the proto-oncoprotein at the physiological level, in both transformed and unaffected tissues. Given the recent paradigm shift in regard to how oncoproteins promote transformation, we review the fundamentals of genetics, signalling and pathogenesis underlying oncoprotein duality.
Topics: Animals; Cell Transformation, Neoplastic; Congenital Abnormalities; Disease Models, Animal; Gene-Environment Interaction; Genetic Diseases, Inborn; Humans; Mice; Mutation; Neoplasms; Proto-Oncogene Proteins; Signal Transduction
PubMed: 32341551
DOI: 10.1038/s41568-020-0256-z -
Molecular Cancer Research : MCR Sep 2014Serine/Arginine Splicing Factor 1 (SRSF1) is the archetype member of the SR protein family of splicing regulators. Since its discovery over two decades ago, SRSF1 has... (Review)
Review
Serine/Arginine Splicing Factor 1 (SRSF1) is the archetype member of the SR protein family of splicing regulators. Since its discovery over two decades ago, SRSF1 has been repeatedly surprising and intriguing investigators by the plethora of complex biologic pathways it regulates. These include several key aspects of mRNA metabolism, such as mRNA splicing, stability, and translation, as well as other mRNA-independent processes, such as miRNA processing, protein sumoylation, and the nucleolar stress response. In this review, the structural features of SRSF1 are discussed as they relate to the intricate mechanism of splicing and the multiplicity of functions it performs. Similarly, a list of relevant alternatively spliced transcripts and SRSF1 interacting proteins is provided. Finally, emphasis is given to the deleterious consequences of overexpression of the SRSF1 proto-oncogene in human cancers, and the complex mechanisms and pathways underlying SRSF1-mediated transformation. The accumulated knowledge about SRSF1 provides critical insight into the integral role it plays in maintaining cellular homeostasis and suggests new targets for anticancer therapy. Mol Cancer Res; 12(9); 1195-204. ©2014 AACR.
Topics: Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neoplasms; Nuclear Proteins; Oncogene Proteins; Proto-Oncogene Mas; RNA; RNA Splicing; RNA, Messenger; RNA-Binding Proteins; Serine-Arginine Splicing Factors
PubMed: 24807918
DOI: 10.1158/1541-7786.MCR-14-0131 -
Molecular Cancer Aug 2003The Ets1 proto-oncoprotein is a member of the Ets family of transcription factors that share a unique DNA binding domain, the Ets domain. The DNA binding activity of... (Review)
Review
The Ets1 proto-oncoprotein is a member of the Ets family of transcription factors that share a unique DNA binding domain, the Ets domain. The DNA binding activity of Ets1 is controlled by kinases and transcription factors. Some transcription factors, such as AML-1, regulate Ets1 by targeting its autoinhibitory module. Others, such as Pax-5, alter Ets1 DNA binding properties. Ets1 harbors two phosphorylation sites, threonine-38 and an array of serines within the exon VII domain. Phosphorylation of threonine-38 by ERK1/2 activates Ets1, whereas phosphorylation of the exon VII domain by CaMKII or MLCK inhibits Ets1 DNA binding activity. Ets1 is expressed by numerous cell types. In haemotopoietic cells, it contributes to the regulation of cellular differentiation. In a variety of other cells, including endothelial cells, vascular smooth muscle cells and epithelial cancer cells, Ets1 promotes invasive behavior. Regulation of MMP1, MMP3, MMP9 and uPA as well as of VEGF and VEGF receptor gene expression has been ascribed to Ets1. In tumors, Ets1 expression is indicative of poorer prognosis.
Topics: Animals; Apoptosis; Gene Expression Regulation; Humans; Neoplasms; Protein Binding; Proto-Oncogene Mas; Proto-Oncogene Protein c-ets-1; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ets; Transcription Factors
PubMed: 12971829
DOI: 10.1186/1476-4598-2-29 -
Cellular and Molecular Life Sciences :... Jan 1999The p53 protein is activated in response to physiological stress resulting in either a G1 arrest of cells or apoptosis. As such, p53 must be tightly regulated, and the... (Review)
Review
The p53 protein is activated in response to physiological stress resulting in either a G1 arrest of cells or apoptosis. As such, p53 must be tightly regulated, and the MDM2 oncoprotein plays a central role in that regulatory process. The transcription of the Mdm2 oncogene is induced by the p53 protein after DNA damage, and the MDM2 protein then binds to p53 and blocks its activities as a tumour suppressor and promotes its degradation. These two proteins thus form an autoregulatory feedback loop in which p53 positively regulates MDM2 levels and MDM2 negatively regulates p53 levels and activity. Immediately after ultraviolet (UV) irradiation MDM2 messenger RNA and protein levels fall in a p53-independent fashion, resulting in increased p53 levels. The p53 protein is then activated as a transcription factor by posttranslational modification permitting p53 to initiate its cell-cycle arrest or apoptotic (programmed cell death) functions. At later times, after the repair of DNA, MDM2 levels increase in a p53-dependent fashion. This induction of MDM2 results in the inhibition of p53 transcriptional activity and the degradation of p53 protein. MDM2-p53 complexes in the nucleus are transported to the cytoplasm via signals present in the MDM2 protein, where p53 is degraded in the proteasome. Thus MDM2 acts as a nuclear-cytoplasmic shuttle for the p53 protein. There are many levels at which this process is regulated, and as such there are many places for chemotherapeutic interventions. The amino-terminal domain of the MDM2 protein is all that is required to bind the p53 protein. The MDM2 protein has additional domains and therefore may have additional functions. Any of these MDM2 domains may contribute to MDM2's activities as an oncogene independent of its inhibition of the tumour suppressor functions of p53. Thus MDM2 itself could be a target for cancer therapeutic intervention.
Topics: Amino Acid Sequence; Animals; Cell Cycle; Feedback; Models, Molecular; Molecular Sequence Data; Nuclear Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Sequence Alignment; Transcription, Genetic; Tumor Suppressor Protein p53; Vertebrates
PubMed: 10065155
DOI: 10.1007/s000180050273 -
International Journal of Molecular... Apr 2023Vaginal dysbiosis is characterized by a decrease in the relative abundance of species in favor of other species. This condition facilitates infections by sexually...
Vaginal dysbiosis is characterized by a decrease in the relative abundance of species in favor of other species. This condition facilitates infections by sexually transmitted pathogens including high risk (HR)-human papilloma viruses (HPVs) involved in the development of cervical cancer. Some vaginal dysbiosis bacteria contribute to the neoplastic progression by inducing chronic inflammation and directly activating molecular pathways involved in carcinogenesis. In this study, SiHa cells, an HPV-16-transformed epithelial cell line, were exposed to different representative vaginal microbial communities. The expression of the HPV oncogenes and and the production of relative oncoproteins was evaluated. The results showed that and modulated the basal expression of the and genes of SiHa cells and the production of the E6 and E7 oncoproteins. Vaginal dysbiosis bacteria had contrasting effects on gene expression and protein production. The expression of the and genes and the production of the relative oncoproteins was increased by strains of and, to a lesser extent, by In contrast, decreased the expression of oncogenes and the production of the E7 protein. A decreased amount of p53 and pRb was found in the cultures of SiHa cells with , and accordingly, in the same cultures, a higher percentage of cells progressed to the S-phase of the cell cycle compared to the untreated or -stimulated cultures. These data confirm that represents the most protective component of the vaginal microbiota against neoplastic progression of HR-HPV infected cells, while and, to a lesser extent, may directly interfere in the oncogenic process, inducing or maintaining the production of viral oncoproteins.
Topics: Female; Humans; Human papillomavirus 16; Tumor Suppressor Protein p53; Papillomavirus Infections; Dysbiosis; Repressor Proteins; Papillomavirus E7 Proteins; Oncogene Proteins, Viral; Bacteria; Uterine Cervical Neoplasms
PubMed: 37108333
DOI: 10.3390/ijms24087173 -
Viruses Sep 2022Human papillomaviruses (HPVs) cause a substantial amount of human disease from benign disease such as warts to malignant cancers including cervical carcinoma, head and... (Review)
Review
Human papillomaviruses (HPVs) cause a substantial amount of human disease from benign disease such as warts to malignant cancers including cervical carcinoma, head and neck cancer, and non-melanoma skin cancer. Our ability to model HPV-induced malignant disease has been impeded by species specific barriers and pre-clinical animal models have been challenging to develop. The recent discovery of a murine papillomavirus, MmuPV1, that infects laboratory mice and causes the same range of malignancies caused by HPVs provides the papillomavirus field the opportunity to test mechanistic hypotheses in a genetically manipulatable laboratory animal species in the context of natural infections. The E6 and E7 proteins encoded by high-risk HPVs, which are the HPV genotypes associated with human cancers, are multifunctional proteins that contribute to HPV-induced cancers in multiple ways. In this review, we describe the known activities of the MmuPV1-encoded E6 and E7 proteins and how those activities relate to the activities of HPV E6 and E7 oncoproteins encoded by mucosal and cutaneous high-risk HPV genotypes.
Topics: Female; Humans; Mice; Animals; Papillomavirus Infections; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Alphapapillomavirus; Papillomaviridae; Uterine Cervical Neoplasms
PubMed: 36298698
DOI: 10.3390/v14102138 -
Virology Jan 2013The identification of interactions between viral and host cellular proteins has provided major insights into papillomavirus research, and these interactions are... (Review)
Review
The identification of interactions between viral and host cellular proteins has provided major insights into papillomavirus research, and these interactions are especially relevant to the role of papillomaviruses in the cancers with which they are associated. Recent advances in mass spectrometry technology and data processing now allow the systematic identification of such interactions. This has led to an improved understanding of the different pathologies associated with the many papillomavirus types, and the diverse nature of these viruses is reflected in the spectrum of interactions with host proteins. Here we review a history of proteomic approaches, particularly as applied to the papillomaviruses, and summarize current techniques. Current proteomic studies on the papillomaviruses use yeast-two-hybrid or affinity purification-mass spectrometry approaches. We detail the advantages and disadvantages of each and describe current examples of papillomavirus proteomic studies, with a particular focus on the HPV E6 and E7 oncoproteins.
Topics: Binding Sites; Genetic Variation; Host-Pathogen Interactions; Humans; Mass Spectrometry; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus E7 Proteins; Papillomavirus Infections; Phylogeny; Protein Binding; Protein Interaction Mapping; Proteome; Two-Hybrid System Techniques
PubMed: 23217616
DOI: 10.1016/j.virol.2012.09.046 -
Cell Nov 2020KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing... (Review)
Review
KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing pursuit in precision oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in ∼13% of lung adenocarcinomas and, at a lower frequency, in other cancers. Preclinical studies describing their discovery and mechanism of action, coupled with emerging clinical data from patients treated with these drugs, have sparked a renewed enthusiasm in the study of KRAS and its therapeutic potential. Here, we discuss how these advances are reshaping the fundamental aspects of KRAS oncoprotein biology and the strides being made toward improving patient outcomes in the clinic.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Mutation; Proto-Oncogene Proteins p21(ras)
PubMed: 33065029
DOI: 10.1016/j.cell.2020.09.044 -
Journal of Virology Nov 2022The human papillomavirus (HPV) E6 and E7 oncogenes are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk...
The human papillomavirus (HPV) E6 and E7 oncogenes are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how HPV16 E6 and E7 alter the cellular response to the proinflammatory cytokine IL-1β. Models of early stage HPV infection and of established HPV-positive head and neck cancers exhibited similar dysregulation of IL-1 pathway genes and suppressed transcriptional responses to IL-1β treatment. Such overlap in cell responses supports that changes induced by HPV16 E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV16 E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1β-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells. Human papillomavirus (HPV) infection is responsible for nearly 5% of the worldwide cancer burden. HPV-positive tumors develop over years to decades in tissues that are subject to frequent stimulation by proinflammatory cytokines. However, the effects of HPV oncoproteins on the cellular response to cytokine stimulation are not well defined. We analyzed IL-1 cytokine signaling in several models of HPV biology and disease. We found that HPV16 E6 and E7 oncoproteins mediate a broad and potent suppression of cellular responses to IL-1β in models of both early and late stages of carcinogenesis. Our data provide a resource for future investigation of IL-1 signaling in HPV-positive cells and cancers.
Topics: Humans; Human papillomavirus 16; Papillomavirus Infections; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Papillomaviridae; Carcinogenesis; Tumor Microenvironment
PubMed: 36342298
DOI: 10.1128/jvi.01326-22