Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

Carr, Michael I.; Jones, Stephen N.

doi:10.21037/tcr.2016.11.75

Cited by 55 publications

(51 citation statements)

References 249 publications

(238 reference statements)

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“…Since p53 protein is a substrate of USP10, we further evaluated p14ARF/CDKN2A which is a well-known tumour suppressor protein mediating oncogenic p53 activation. p14ARF binds to MDM2 and stabilizes p53 when there is DNA damage or cellular stress (39,40). Although, there are numerous reports about transcriptional silencing of the p14ARF/CDKN2A gene through DNA promoter hypermethylation in many cancers, Ko et al (14) have recently reported that c-Myc protein influences the stabilization of p14ARF by activating USP10 transcription.…”

Section: Discussionmentioning

confidence: 99%

Loss of Both USP10 and p14ARF Protein Expression Is an Independent Prognostic Biomarker for Poor Prognosis in Patients With Epithelial Ovarian Cancer

Han

Chay

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: The prognostic role of USP10 in epithelial ovarian cancer has been studied in various human cancers. Our aim was to evaluate the clinical and pathological significance of USP10 in epithelial ovarian cancer. Materials and Methods: Immunohistochemical analyses of the expression of USP10 and p14ARF by using tissue microarrays were performed in 336 ovarian tumours and the data were compared with clinicopathological variables. We examined their level of DNA methylation around the putative transcriptional start site in 5' CpG islands in fresh frozen tissues and ovarian cancer cells. Results: Expression of USP10 and p14ARF was significantly lower in cancer tissues than in normal epithelium. Low USP10 expression and a combined USP10/p14ARF low expression were revealed to be independent prognostic factors. A high degree of methylation in USP10 and p14ARF CpG islands was found by methylation specific PCR analysis in cancer than in normal tissues and cells. Conclusion: Decreased expression of USP10 or combined USP10/p14ARF decreased expression is a strong indicator of poor prognosis in patients with ovarian cancer. Epithelial ovarian cancer (EOC) is one of the most common gynaecological cancer. It is one of the most lethal diseases among the top five leading causes of cancer-related death in women (1). Advanced EOC patients exhibit only 40% of 5year survival rate (2). Surgical cytoreduction followed by adjuvant combined chemotherapy is the standard treatment of EOC patients. Despite the improvement in treatment modalities, most women with EOC experience relapse and eventually die from the disease. One of the major limitations to successful treatment is development of acquired resistance against the chemotherapeutic agent. Consequently, understanding the molecular mechanisms of EOC and the availability of predictive biomarkers for chemosensitivity of EOC would lead to the development of more specific prognostic markers to improve patient survival. Ubiquitination and de-ubiquitination are important posttranslational modifications which regulate activation, localization and degradation of proteins through conjugating or deconjugating ubiquitin from substrate proteins (3). Ubiquitin-specific protease10 (USP10), a member of the ubiquitin-specific protease (USP) family, regulates crucial signalling factors for cellular growth and apoptosis (4, 5). Recently, several studies have reported USP10 as a novel regulator of p53 in cancers (6). It has also been reported that it contributes to tumorigenesis in several types of cancers, such as breast cancer, stomach cancer, and glioblastoma (7-9). p14ARF located in the INK4a/ARF locus at chromosome 9q21 is an alternative reading frame product that encodes p16protein (10). It is a potent tumour suppressor which stabilizes p53 that induces cellular senescence and prevents tumour cell growth. Down-regulation or deletion of p14ARF in various cancers, including breast, lung and gastric, has been reported (11-13). Recently, Ko et al. (14) demonstrated that USP10 and/or p14ARF are...

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Section: Discussionmentioning

confidence: 99%

Loss of Both USP10 and p14ARF Protein Expression Is an Independent Prognostic Biomarker for Poor Prognosis in Patients With Epithelial Ovarian Cancer

Han

Chay

et al. 2019

Cancer Genomics Proteomics

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“…Although many proteins are directly involved in the regulation of p53 levels and functioning, it is generally accepted that MDM2 is the principal negative regulator of p53 (37). Serving as an E3 ubiquitin ligase of p53, MDM2 not only negatively regulates p53 activity through the induction of p53 protein degradation (38), but directly inhibits p53 trans-action on chromatin (39).…”

Section: Discussionmentioning

confidence: 99%

JIB‑04 induces cell apoptosis via activation of the p53/Bcl‑2/caspase pathway in MHCC97H and HepG2 cells

Liao

Liu

et al. 2018

Oncol Rep

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JIB-04 is a structurally unique small molecule, known to exhibit anticancer activity and to inhibit the growth of human lung cancer and prostate cancer cell lines. However, the anticancer effect of JIB-04 against human hepatic carcinoma, and its underlying mechanisms, are still unclear. In the present study, MHCC97H and HepG2 cells were employed to investigate the anticancer effects of JIB-04 on cell viability and apoptosis. Annexin V/PI staining, a CCK-8 assay and western blot analysis demonstrated that JIB-04 induced apoptosis in MHCC97H and HepG2 cells, which was evidenced by the expression of proapoptotic and apoptotic proteins including p53, Bak, Bax, caspase-3 and caspase-9. Subsequently, the expression trends of Bcl-2 and p53 were reversed after co-treatment with pifithrin-α (PFT-α, a p53 inhibitor). The results revealed that JIB-04 suppressed the cell viability of MHCC97H and HepG2 cells in a concentration-dependent manner. Meanwhile, it was also demonstrated that JIB-04 effectively triggered MHCC97H and HepG2 cell apoptosis by downregulating Bcl-2/Bax expression, and upregulating proapoptotic and apoptotic protein expression via the p53/Bcl2/caspase signaling pathway. JIB-04 had effects on the inhibition of cell viability and the induction of apoptosis in MHCC97H and HepG2 cells. The underlying mechanism of action of JIB-04 was associated with the p53/Bcl-2/caspase signaling pathway. Our findings provide a foundation for understanding the anticancer effect of JIB-04 on MHCC97H and HepG2 cells, and suggested that JIB-04 may be a promising therapeutic agent in human liver cancer.

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“…It is commonly assumed, in part on the basis of transfection and/or overexpression studies, that viral protein targeting of USP7 will negatively impact p53 expression, generally induced upon virus infection and replication and inhibitory to virus production. However, our own studies in the context of infected cells have failed to identify any USP7 binding-dependent effects of vIRF-1 and vIRF-3 on p53 levels in latently infected PEL cells and during lytic reactivation in these and/or HHV-8 ϩ iSLK cells; indeed, depletion of USP7, which regulates p53 stability through the relative deubiquitination of p53 and its E3 ubiquitin ligase MDM2 (29,52), while phenotypically significant in PEL latency and HHV-8 productive replication, did not detectably alter p53 expression (27). Also in the present study, p53 levels were indistinguishable between iSLK cultures infected with wild-type HHV-8 and mutated virus expressing USP7refractory vIRF-2.S 247 A (Fig.…”

Section: Discussionmentioning

confidence: 87%

“…USP7 is a known deubiquitinase of both p53 and its E3 ubiquitin ligase MDM2, stabilizing both substrates via removal of K48-linked polyubiquitin adducts. When p53-and MDM2-targeting ATM kinase is inactive, the affinity of USP7 for MDM2 is higher than it is for p53; under conditions of DNA damage response activation, however, the reverse is true and p53 is stabilized by ATM phosphorylation of MDM2 (and associated MDMX/MDM4) and consequent reduced USP7 binding to the p53 regulator (29). The interactions of all HHV-8 vIRFs with USP7 suggest that p53 regulation, and the resulting apoptotic inhibition, is a common node of vIRF activity in the context of infection.…”

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confidence: 99%

USP7-Dependent Regulation of TRAF Activation and Signaling by a Viral Interferon Regulatory Factor Homologue

Xiang

Nicholas

2020

J Virol

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Human herpesvirus 8 (HHV-8) encodes four viral interferon regulatory factors (vIRFs 1 to 4), all of which are expressed during lytic replication and inhibit a variety of antiviral signaling pathways. Viral IRFs 1, 2, and 3 are also expressed during latency in primary effusion lymphoma (PEL) cells, and vIRF-1 and vIRF-3 have been reported to promote PEL cell viability. Viral IRFs 1, 3, and 4 are known to interact with ubiquitin-specific protease 7 (USP7); interactions of vIRF-1 and vIRF-3 with USP7 promote PEL cell viability and regulate productive replication. Here, we report that vIRF-2 also targets USP7, utilizing a PSTS motif matching the USP7 N-terminal domain-binding A/PxxS consensus, but uniquely requires catalytic domain residues for intracellular interaction. In functional and mechanistic analyses, tumor necrosis factor receptor-associated factor (TRAF)-mediated signaling and associated polyubiquitination of TRAFs 3 and 6, specifically, were regulated negatively by USP7 and positively by vIRF-2-USP7 interaction, the latter competing for USP7-TRAF association. Using depletion, depletion-complementation, and targeted mutagenesis approaches, vIRF-2 was determined to promote latent PEL cell viability, likely independently of USP7 interaction, while lytic replication was inhibited by vIRF-2, in part or in whole via USP7 interaction. Together, our data identify a new molecular determinant of USP7 recognition, TRAF3/6-specific targeting by the deubiquitinase, associated activation of these TRAFs by vIRF-2, and activities of vIRF-2 and vIRF-2-USP7 interaction in HHV-8 latent and lytic biology. IMPORTANCE Human herpesvirus 8-encoded IRF homologues were the first to be identified in a virus. Through inhibitory interactions with cellular IRFs and other mediators of antiviral signaling, the vIRFs are believed to be essential for productive replication and also for latency in particular cell types. The deubiquitinase USP7 is a regulator of key cellular pathways, modulates HHV-8 latent and lytic infection, and is targeted by vIRFs 1, 3, and 4. Here, we report that vIRF-2 also interacts with USP7, via a means distinguishable from USP7 interactions with other vIRFs and other proteins, that this interaction modulates antiviral signaling via disruption of USP7 interactions with innate immune signaling proteins TRAF3 and TRAF6, and that vIRF-2 targeting of USP7 regulates HHV-8 productive replication. The presented data are the first to identify vIRF-2 targeting of USP7 and its role in HHV-8 biology, expanding our understanding of the repertoire and importance of virus-host interactions.

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Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

Cited by 55 publications

References 249 publications

Loss of Both USP10 and p14ARF Protein Expression Is an Independent Prognostic Biomarker for Poor Prognosis in Patients With Epithelial Ovarian Cancer

Loss of Both USP10 and p14ARF Protein Expression Is an Independent Prognostic Biomarker for Poor Prognosis in Patients With Epithelial Ovarian Cancer

JIB‑04 induces cell apoptosis via activation of the p53/Bcl‑2/caspase pathway in MHCC97H and HepG2 cells

USP7-Dependent Regulation of TRAF Activation and Signaling by a Viral Interferon Regulatory Factor Homologue

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