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Mutation Research. Reviews in Mutation... 2017Human Papillomaviruses (HPVs) are double-stranded DNA viruses, that infect epithelial cells and are etiologically involved in the development of human cancer. Today,... (Review)
Review
Human Papillomaviruses (HPVs) are double-stranded DNA viruses, that infect epithelial cells and are etiologically involved in the development of human cancer. Today, over 200 types of human papillomaviruses are known. They are divided into low-risk and high-risk HPVs depending on their potential to induce carcinogenesis, driven by two major viral oncoproteins, E6 and E7. By interacting with cellular partners, these proteins are involved in interdependent viral and cell cycles in stratified differentiating epithelium, and concomitantly induce epigenetic changes in infected cells and those undergoing malignant transformation. E6 and E7 oncoproteins interact with and/or modulate expression of many proteins involved in epigenetic regulation, including DNA methyltransferases, histone-modifying enzymes and subunits of chromatin remodeling complexes, thereby influencing host cell transcription program. Furthermore, HPV oncoproteins modulate expression of cellular micro RNAs. Most of these epigenetic actions in a complex dynamic interplay participate in the maintenance of persistent infection, cell transformation, and development of invasive cancer by a considerable deregulation of tumor suppressor and oncogenes. In this study, we have undertaken to discuss a number of studies concerning epigenetic regulations in HPV-dependent cells and to focus on those that have biological relevance to cancer progression.
Topics: Carcinogenesis; DNA Methylation; DNA, Viral; Epigenesis, Genetic; Gene Expression Regulation, Viral; Genome, Viral; Humans; MicroRNAs; Neoplasms; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus E7 Proteins; Papillomavirus Infections
PubMed: 28528689
DOI: 10.1016/j.mrrev.2016.09.006 -
Viruses Jan 2018Since their discovery in the mid-eighties, the main papillomavirus oncoproteins E6 and E7 have been recalcitrant to high-resolution structure analysis. However, in the... (Review)
Review
Since their discovery in the mid-eighties, the main papillomavirus oncoproteins E6 and E7 have been recalcitrant to high-resolution structure analysis. However, in the last decade a wealth of three-dimensional information has been gained on both proteins whether free or complexed to host target proteins. Here, we first summarize the diverse activities of these small multifunctional oncoproteins. Next, we review the available structural data and the new insights they provide about the evolution of E6 and E7, their multiple interactions and their functional variability across human papillomavirus (HPV) species.
Topics: Host-Pathogen Interactions; Humans; Nuclear Magnetic Resonance, Biomolecular; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus E7 Proteins; Protein Structure, Tertiary; Repressor Proteins
PubMed: 29342959
DOI: 10.3390/v10010037 -
Biochemical Pharmacology Feb 2022The Hedgehog (Hh) family of lipid-modified signaling proteins directs embryonic tissue patterning and postembryonic tissue homeostasis, and dysregulated Hh signaling... (Review)
Review
The Hedgehog (Hh) family of lipid-modified signaling proteins directs embryonic tissue patterning and postembryonic tissue homeostasis, and dysregulated Hh signaling drives familial and sporadic cancers. Hh ligands bind to and inhibit the tumor suppressor Patched and allow the oncoprotein Smoothened (SMO) to accumulate in cilia, which in turn activates the GLI family of transcription factors. Recent work has demonstrated that endogenous cholesterol and oxidized cholesterol derivatives (oxysterols) bind and modulate SMO activity. Here we discuss the myriad sterols that activate or inhibit the Hh pathway, with emphasis on endogenous 24(S),25-epoxycholesterol and 3β,5α-dihydroxycholest-7-en-6-one, and propose models of sterol regulation of SMO. Synthetic inhibitors of SMO have long been the focus of drug development efforts. Here, we discuss the possible utility of steroidal SMO ligands or inhibitors of enzymes involved in sterol metabolism as cancer therapeutics.
Topics: Animals; Carcinogenesis; Hedgehog Proteins; Humans; Oncogene Proteins; Signal Transduction; Smoothened Receptor; Sterols
PubMed: 34111427
DOI: 10.1016/j.bcp.2021.114647 -
Viruses Apr 2019Papillomaviruses replicate and cause disease in stratified squamous epithelia. Epithelial differentiation is essential for the progression of papillomavirus replication,... (Review)
Review
Papillomaviruses replicate and cause disease in stratified squamous epithelia. Epithelial differentiation is essential for the progression of papillomavirus replication, but differentiation is also impaired by papillomavirus-encoded proteins. The papillomavirus E6 and E7 oncoproteins partially inhibit and/or delay epithelial differentiation and some of the mechanisms by which they do so are beginning to be defined. This review will outline the key features of the relationship between HPV infection and differentiation and will summarize the data indicating that papillomaviruses alter epithelial differentiation. It will describe what is known so far and will highlight open questions about the differentiation-inhibitory mechanisms employed by the papillomaviruses.
Topics: Animals; Cell Differentiation; Cell Transformation, Viral; Epithelial Cells; Human papillomavirus 16; Humans; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Repressor Proteins; Virus Replication
PubMed: 31013597
DOI: 10.3390/v11040369 -
Oncotarget May 2016The RNA helicase A (RHA) is involved in several steps of RNA metabolism, such as RNA processing, cellular transit of viral molecules, ribosome assembly, regulation of... (Review)
Review
The RNA helicase A (RHA) is involved in several steps of RNA metabolism, such as RNA processing, cellular transit of viral molecules, ribosome assembly, regulation of transcription and translation of specific mRNAs. RHA is a multifunctional protein whose roles depend on the specific interaction with different molecular partners, which have been extensively characterized in physiological situations. More recently, the functional implication of RHA in human cancer has emerged. Interestingly, RHA was shown to cooperate with both tumor suppressors and oncoproteins in different tumours, indicating that its specific role in cancer is strongly influenced by the cellular context. For instance, silencing of RHA and/or disruption of its interaction with the oncoprotein EWS-FLI1 rendered Ewing sarcoma cells more sensitive to genotoxic stresses and affected tumor growth and maintenance, suggesting possible therapeutic implications. Herein, we review the recent advances in the cellular functions of RHA and discuss its implication in oncogenesis, providing a perspective for future studies and potential translational opportunities in human cancer.
Topics: Cell Transformation, Neoplastic; DEAD-box RNA Helicases; DNA Damage; Humans; Neoplasm Proteins; Oncogene Proteins, Fusion; Protein Binding; Proto-Oncogene Protein c-fli-1; Proto-Oncogene Proteins; RNA Interference; RNA-Binding Protein EWS; Sarcoma, Ewing; Tumor Suppressor Proteins
PubMed: 26885691
DOI: 10.18632/oncotarget.7377 -
Molecular & Cellular Proteomics : MCP Apr 2017Oncogenic viruses are responsible for about 15% human cancers. This article explores the promise and challenges of viral proteomics in the study of the oncogenic human... (Review)
Review
Oncogenic viruses are responsible for about 15% human cancers. This article explores the promise and challenges of viral proteomics in the study of the oncogenic human DNA viruses, HPV, McPyV, EBV and KSHV. These viruses have coevolved with their hosts and cause persistent infections. Each virus encodes oncoproteins that manipulate key cellular pathways to promote viral replication and evade the host immune response. Viral proteomics can identify cellular pathways perturbed by viral infection, identify cellular proteins that are crucial for viral persistence and oncogenesis, and identify important diagnostic and therapeutic targets.
Topics: DNA Virus Infections; Host-Pathogen Interactions; Humans; Neoplasms; Oncogene Proteins; Oncogenic Viruses; Proteomics; Viral Proteins; Virus Replication
PubMed: 28104704
DOI: 10.1074/mcp.O116.065201 -
Biomolecular Concepts Mar 2014MDM2 is an oncoprotein that blocks p53 tumor suppressor-mediated transcriptional transactivation, escorts p53 from the cell nucleus to the cytoplasm, and... (Review)
Review
MDM2 is an oncoprotein that blocks p53 tumor suppressor-mediated transcriptional transactivation, escorts p53 from the cell nucleus to the cytoplasm, and polyubiquitylates p53. Polyubiquitylated p53 is rapidly degraded in the cytoplasm by the 26S proteasome. MDM2 is abnormally upregulated in several types of cancers, especially those of mesenchymal origin. MDM4 is a homolog of MDM2 that also inhibits p53 by blocking p53-mediated transactivation. MDM4 is required for MDM2-mediated polyubiquitylated of p53 and is abnormally upregulated in several cancer types. MDM2 and MDM4 genes have been detected in all vertebrates to date and only a single gene homolog, named MDM, has been detected in some invertebrates. MDM2, MDM4, and MDM have similar gene structures, suggesting that MDM2 and MDM4 arose through a duplication event more than 440 million years ago. All members of this small MDM2 gene family contain a single really interesting new gene (RING) domain (with the possible exception of lancelet MDM) which places them in the RING-domain superfamily. Similar to MDM2, the vast majority of proteins with RING domains are E3 ubiquitin ligases. Other RING domain E3 ubiquitin ligases that target p53 are COP1, Pirh2, and MSL2. In this report, we present evidence that COP1, Pirh2, and MSL2 evolved independently of MDM2 and MDM4. We also show, through structure homology models of invertebrate MDM RING domains, that MDM2 is more evolutionarily conserved than MDM4.
Topics: Animals; Cell Cycle Proteins; Humans; Models, Molecular; Multigene Family; Nuclear Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; RING Finger Domains; Structural Homology, Protein
PubMed: 25372739
DOI: 10.1515/bmc-2013-0027 -
Molecular Cancer Mar 2023Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these... (Review)
Review
Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design.
Topics: Humans; Proteolysis; Oncogene Proteins; Transcription Factors; Ubiquitin-Protein Ligases; Neoplasms
PubMed: 36991452
DOI: 10.1186/s12943-022-01707-5 -
The Journal of Biological Chemistry Apr 2020Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein-coupled receptors (GPCRs) to intracellular... (Review)
Review
Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein-coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the G family-specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of G oncoproteins, mutant G variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike G oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting G protein oncogenes as well as broaden our mechanistic understanding of G protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G proteins as targets in drug discovery efforts.
Topics: Animals; Antineoplastic Agents; Depsipeptides; Drug Discovery; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Oncogene Proteins; Signal Transduction
PubMed: 32122969
DOI: 10.1074/jbc.REV119.007061 -
Cellular Signalling 1997Studies of the roles of oncoproteins in cell cycle progression have concentrated on G1 because transformation is frequently associated with loss of G1 checkpoint... (Review)
Review
Studies of the roles of oncoproteins in cell cycle progression have concentrated on G1 because transformation is frequently associated with loss of G1 checkpoint control. However, it has become evident that G2 and mitotic checkpoints are often compromised in transformed cells and that many tumour suppressor proteins and oncoprotein kinases regulate and/or are activated in G2 and M. Disruption of p53 and ATM tumour suppressor protein functions can eliminate G2 and M checkpoints. The Src family kinases are activated in mitosis and collectively play an indispensable role in progression through G2/M. In addition, evidence suggests that Mos and elements of the Ras/Raf/MAPK cascade are also active in mitosis and appear likely to regulate G2 and/or M. Potential targets of these kinases include likely regulators of gene expression and microtubule dynamics such as Sam68 and Oncoprotein 18/stathmin. The ability of some oncoproteins to perturb orderly progression through both G1 and/or S and G2 and/or M is probably important for transformation.
Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA-Binding Proteins; Humans; Mitosis; Oncogene Proteins; Protein Kinases; Protein Serine-Threonine Kinases; Proteins; Signal Transduction; Tumor Suppressor Protein p53; Tumor Suppressor Proteins
PubMed: 9218124
DOI: 10.1016/s0898-6568(96)00176-3