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Theranostics 2023Whatever the mucosa primary infected, HPV-positive cancers are traditionally associated with a favorable outcome, attributable to a high sensitivity to radiation...
Whatever the mucosa primary infected, HPV-positive cancers are traditionally associated with a favorable outcome, attributable to a high sensitivity to radiation therapy. However, the direct impact of viral E6/E7 oncoproteins on the intrinsic cellular radiosensitivity (and, globally, on host DNA repair) remains mostly speculative. Using several isogenic cell models expressing HPV16 E6 and/or E7, the effect of viral oncoproteins on global DNA damage response was first investigated by approaches. The binary interactome of each individual HPV oncoprotein with factors involved in the various host DNA damage/repair mechanisms was then precisely mapped by luciferase complementation assay (and validated by co-immunoprecipitation). The stability/half-life of protein targets for HPV E6 and/or E7 as well as their subcellular localizations were determined. At last, the host genome integrity following E6/E7 expression and the synergy between radiotherapy and compounds targeting DNA repair were analyzed. We first showed that the sole expression of one viral oncoprotein from HPV16 was able to significantly increase the sensitivity to irradiation of cells without affecting their basal viability parameters. In total, 10 novel targets (CHEK2, CLK2, CLK2/3, ERCC3, MNAT1, PER1, RMI1, RPA1, UVSSA and XRCC6) for E6 and 11 (ALKBH2, CHEK2, DNA2, DUT, ENDOV, ERCC3, PARP3, PMS1, PNKP, POLDIP2 and RBBP8) for E7 were identified. Importantly, not degraded following their interaction with E6 or E7, these proteins have been shown to be less linked to host DNA and to colocalize with HPV replication foci, denoting their crucial implication in viral life cycle. Finally, we found that E6/E7 oncoproteins globally jeopardize host genome integrity, increase the cellular sensitivity to DNA repair inhibitors and enhance their synergy with radiotherapy. Taken together, our findings provide a molecular insight into the direct hijacking of host DNA damage/repair responses by HPV oncoproteins, demonstrate the significant impact of this phenomenon on both intrinsic cellular radiosensitivity and host DNA integrity and suggest novel connected therapeutic vulnerabilities.
Topics: Humans; Human Papillomavirus Viruses; Papillomavirus Infections; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; DNA Repair; DNA Damage; Neoplasms; Nuclear Proteins; Phosphotransferases (Alcohol Group Acceptor); DNA Repair Enzymes; Carrier Proteins
PubMed: 36793865
DOI: 10.7150/thno.78091 -
Scandinavian Journal of Work,... 1992It seems increasingly likely that an important mechanism of action of certain workplace carcinogens in contributing to occupational carcinogenesis may be via the... (Review)
Review
It seems increasingly likely that an important mechanism of action of certain workplace carcinogens in contributing to occupational carcinogenesis may be via the activation of cellular oncogenes, which then cause an expression of mutated forms or increased amounts of their oncoprotein products. Two prototypical models of this mechanism may be the ras oncogene and its p21 protein and the neu oncogene and its p185 protein. Both are known to be activated by exposure to common occupational carcinogens, and both are known to occur frequently in human tumors, including those of occupational concern such as lung cancer. Knowledge of their mechanisms of action may lead to new opportunities for preventing occupational cancer.
Topics: Animals; Genes, ras; Humans; Neoplasms; Occupational Diseases; Oncogene Protein p21(ras); Oncogenes; Proto-Oncogene Proteins; Proto-Oncogenes; Receptor, ErbB-2; Retroviridae
PubMed: 1357742
DOI: No ID Found -
Biochimica Et Biophysica Acta Aug 2012The homologous ETV1, ETV4 and ETV5 proteins form the PEA3 subfamily of ETS transcription factors. In Ewing tumors, chromosomal translocations affecting ETV1 or ETV4 are... (Review)
Review
The homologous ETV1, ETV4 and ETV5 proteins form the PEA3 subfamily of ETS transcription factors. In Ewing tumors, chromosomal translocations affecting ETV1 or ETV4 are an underlying cause of carcinogenesis. Likewise, chromosomal rearrangements of the ETV1, ETV4 or ETV5 gene occur in prostate tumors and are thought to be one of the major driving forces in the genesis of prostate cancer. In addition, these three ETS proteins are implicated in melanomas, breast and other types of cancer. Complex posttranslational modifications govern the activity of PEA3 factors, which can promote cell proliferation, motility and invasion. Here, we review evidence for a role of ETV1, 4 and 5 as oncoproteins and describe modes of their action. Modulation of their activation or interaction with cofactors as well as inhibiting crucial target gene products may ultimately be exploited to treat various cancers that are dependent on the PEA3 group of ETS transcription factors.
Topics: Adenovirus E1A Proteins; Amino Acid Sequence; DNA-Binding Proteins; Humans; Molecular Sequence Data; Neoplasms; Protein Processing, Post-Translational; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ets; Transcription Factors; Translocation, Genetic
PubMed: 22425584
DOI: 10.1016/j.bbcan.2012.02.002 -
Cancer Cell Nov 2017Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two... (Review)
Review
Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins; Oncogene Proteins, Fusion; Tretinoin; Tumor Suppressor Proteins
PubMed: 29136503
DOI: 10.1016/j.ccell.2017.10.002 -
British Journal of Cancer Mar 2024Cervical carcinogenesis is mediated by the HPV-E6 and E7 oncoproteins, considered as biomarkers usable in managing screen-positive women. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cervical carcinogenesis is mediated by the HPV-E6 and E7 oncoproteins, considered as biomarkers usable in managing screen-positive women.
METHODS
We conducted a systematic review and meta-analysis assessing the accuracy of HPV-E6/E7-oncoprotein tests to detect underlying cervical-precancer and cancer. We included studies reporting data on oncoprotein test accuracy detecting cervical intraepithelial neoplasia grade 3 or worse. Random effects logistic regression models were applied for pooling absolute and relative accuracy.
RESULTS
Twenty-two studies were included. Sensitivity and specificity estimates ranged from 54.2% (95%CI: 45.2-63.0) to 69.5% (95%CI:60.8-76.9) and from 82.8% (95%CI: 50.4-95.8) to 99.1 (95%CI: 98.8-99.3), respectively in the population irrespective of HPV status. Higher sensitivity estimates ranging from 60.8% (95%CI: 49.6-70.9) to 75.5% (95%CI: 71.7-78.9) but lower specificity estimates ranging from 83.7% (95%CI: 76.1-89.3) to 92.1% (95%CI: 88.5-94.6) were observed in studies enrolling high-risk-HPV-positive women. Studies recruiting only HIV-positive women showed a pooled sensitivity of 46.9% (95%CI: 30.6-63.9) with a specificity of 98.0% (95%CI: 96.8-98.7).
CONCLUSIONS
The high specificity of oncoprotein tests supports its use for triaging HPV-positive women. However, oncoprotein-negative women would not be recommended to undertake routine screening, requiring further follow-up. Large-scale and longitudinal studies are needed to further investigate the role of E6/E7-oncoprotein detection in predicting the risk of developing cervical pre-cancer and cancer.
Topics: Female; Humans; Papillomavirus Infections; Uterine Cervical Dysplasia; Oncogene Proteins, Viral; Cervix Uteri; Papillomavirus E7 Proteins; Uterine Cervical Neoplasms; Papillomaviridae
PubMed: 37973957
DOI: 10.1038/s41416-023-02490-w -
Asian Pacific Journal of Cancer... 2012High-risk human papillomavirus (HPV) especially HPV-16 and HPV-18 types are speculated to be important risk factors in non-smoking associated lung cancer in Asia.... (Review)
Review
High-risk human papillomavirus (HPV) especially HPV-16 and HPV-18 types are speculated to be important risk factors in non-smoking associated lung cancer in Asia. Increasing evidence has demonstrated that HPV oncoproteins may contribute to lung tumorigenesis and cell transformation. Importantly, HPV 16/18 E6 and E7 oncoproteins can mediate expression of multiple target genes and proteins, such as p53/pRb, VEGF, HIF-1α, cIAP-2, and hTERT, and contribute to cell proliferation, angiogenesis and cell immortalization through different signaling pathways in lung cancer. This article provides an overview of experiment data on HPV-associated lung cancer, describes the main targets on which HPV E6/E7 oncoproteins act, and further discusses the potential signaling pathways in which HPV E6/E7 oncoproteins are involved. In addition, we also raise questions regarding existing problems with the study of HPV-associated lung cancer.
Topics: Animals; Antineoplastic Agents; Cell Transformation, Viral; DNA-Binding Proteins; Humans; Lung Neoplasms; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus E7 Proteins; Repressor Proteins; Smoking
PubMed: 23317184
DOI: 10.7314/apjcp.2012.13.11.5363 -
Biochimica Et Biophysica Acta Aug 2014The changes from normal cells to cancer cells are primarily regulated by genome instability, which foster hallmark functions of cancer through multiple mechanisms... (Review)
Review
The changes from normal cells to cancer cells are primarily regulated by genome instability, which foster hallmark functions of cancer through multiple mechanisms including protein mislocalization. Mislocalization of these proteins, including oncoproteins, tumor suppressors, and other cancer-related proteins, can interfere with normal cellular function and cooperatively drive tumor development and metastasis. This review describes the cancer-related effects of protein subcellular mislocalization, the related mislocalization mechanisms, and the potential application of this knowledge to cancer diagnosis, prognosis, and therapy.
Topics: Animals; Humans; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Oncogene Proteins; Prognosis; Protein Transport; Signal Transduction; Tumor Suppressor Proteins
PubMed: 24709009
DOI: 10.1016/j.bbcan.2014.03.006 -
European Journal of Biochemistry Jan 1993Interest in the Ets proteins has grown enormously over the last decade. The v-ets oncogene was originally discovered as part of a fusion protein expressed by a... (Review)
Review
Interest in the Ets proteins has grown enormously over the last decade. The v-ets oncogene was originally discovered as part of a fusion protein expressed by a transforming retrovirus (avian E26), and later shown to be transduced from a cellular gene. About 30 related proteins have now been found in species ranging from flies to humans, that resemble the vEts protein in the so-called 'ets domain'. The ets domain has been shown to be a DNA-binding domain, that specifically interacts with sequences containing the common core trinucleotide GGA. Furthermore, it is involved in protein-protein interactions with co-factors that help determine its biological activity. Many of the Ets-related proteins have been shown to be transcription activators, like other nuclear oncoproteins and anti-oncoproteins (Jun, Fos, Myb, Myc, Rel, p53, etc.). However, Ets-like proteins may have other functions, such as in DNA replication and a general role in transcription activation. Ets proteins have been implicated in regulation of gene expression during a variety of biological processes, including growth control, transformation, T-cell activation, and developmental programs in many organisms. Signals regulating cell growth are transmitted from outside the cell to the nucleus by growth factors and their receptors. G-proteins, kinases and transcription factors. We will discuss how several Ets-related proteins fit into this scheme, and how their activity is regulated both post- and pre-translationally. Loss of normal control is often associated with conversion to an oncoprotein. vEts has been shown to have different properties from its progenitor, which might explain how it has become oncogenic. Oncogene-related products have been implicated in the control of various developmental processes. Evidence is accumulating for a role for Ets family members in Drosophila development, Xenopus oocyte maturation, lymphocyte differentiation, and viral infectious cycles. An ultimate hope in studying transformation by oncoproteins is to understand how cells become cancerous in humans, which would lead to more effective treatments. vEts induces erythroblastosis in chicken. Cellular Ets-family proteins can be activated by proviral insertion in mice and, most interestingly, by chromosome translocation in humans. We are at the beginning of understanding the multiple facets of regulation of Ets activity. Future work on the Ets family promises to provide important insights into both normal control of growth and differentiation, and deregulation in illness.
Topics: Amino Acid Sequence; Animals; Base Sequence; Binding Sites; Cell Transformation, Neoplastic; Consensus Sequence; DNA Replication; DNA-Binding Proteins; Gene Expression Regulation; Humans; Molecular Sequence Data; Multigene Family; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ets; Proto-Oncogenes; Regulatory Sequences, Nucleic Acid; Sequence Alignment; Sequence Homology, Amino Acid; Transcription Factors; Transcription, Genetic
PubMed: 8425553
DOI: 10.1007/978-3-642-78757-7_2 -
Journal of Experimental & Clinical... Jan 2022The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research,... (Review)
Review
The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the KRAS gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring the KRAS mutation. Adagrasib (MRTX849) and other direct KRAS inhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRAS mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRAS inhibitors and summarize the ongoing clinical trials of all direct KRAS inhibitors.
Topics: Drug Development; Humans; Immunotherapy; Proto-Oncogene Proteins p21(ras)
PubMed: 35045886
DOI: 10.1186/s13046-021-02225-w -
Nature Reviews. Cancer Jul 2016The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors.... (Review)
Review
The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors. Initial studies of these 'spliceosomal mutations' suggest that the proteins bearing these mutations exhibit altered splice site and/or exon recognition preferences relative to their wild-type counterparts, resulting in cancer-specific mis-splicing. Such changes in the splicing machinery may create novel vulnerabilities in cancer cells that can be therapeutically exploited using compounds that can influence the splicing process. Further studies to dissect the biochemical, genomic and biological effects of spliceosomal mutations are crucial for the development of cancer therapies targeted at these mutations.
Topics: Catalysis; Genes, Tumor Suppressor; Humans; Neoplasms; Oncogene Proteins; RNA Splicing Factors
PubMed: 27282250
DOI: 10.1038/nrc.2016.51