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000298616 1001_ $$0P:(DE-He78)b99b271e0ad2dea9ba3ebefc35af9a76$$aAvenhaus, Alicia$$b0$$eFirst author$$udkfz
000298616 245__ $$aE6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence.
000298616 260__ $$aLawrence, Kan.$$bPLoS$$c2025
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000298616 520__ $$aOncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The formation of a trimeric complex between the HPV E6 oncoprotein, the cellular ubiquitin ligase E6AP and the p53 tumor suppressor protein leads to proteolytic p53 degradation and plays a central role for HPV-induced cell transformation. We here uncover that E6AP silencing in HPV-positive cancer cells ultimately leads to efficient induction of cellular senescence, revealing that E6AP acts as a potent anti-senescent factor in these cells. Thus, although the downregulation of either E6 or E6AP expression also acts partially pro-apoptotic, HPV-positive cancer cells surviving E6 repression proliferate further, whereas they become irreversibly growth-arrested upon E6AP repression. We moreover show that the senescence induction following E6AP downregulation is mechanistically highly dependent on induction of the p53/p21 axis, other than the known pro-senescent response of HPV-positive cancer cells following combined downregulation of the viral E6 and E7 oncoproteins. Of further note, repression of E6AP allows senescence induction in the presence of the anti-senescent HPV E7 protein. Yet, despite these mechanistic differences, the pathways underlying the pro-senescent effects of E6AP or E6/E7 repression ultimately converge by being both dependent on the cellular pocket proteins pRb and p130. Taken together, our results uncover a hitherto unrecognized and potent anti-senescent function of the E6AP protein in HPV-positive cancer cells, which is essential for their sustained proliferation. Our results further indicate that interfering with E6AP expression or function could result in therapeutically desired effects in HPV-positive cancer cells by efficiently inducing an irreversible growth arrest. Since the critical role of the E6/E6AP/p53 complex for viral transformation is conserved between different oncogenic HPV types, this approach could provide a therapeutic strategy, which is not HPV type-specific.
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000298616 650_7 $$2NLM Chemicals$$aOncogene Proteins, Viral
000298616 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aUbiquitin-Protein Ligases
000298616 650_7 $$0EC 2.3.2.26$$2NLM Chemicals$$aUBE3A protein, human
000298616 650_7 $$2NLM Chemicals$$aTumor Suppressor Protein p53
000298616 650_7 $$2NLM Chemicals$$aRepressor Proteins
000298616 650_7 $$2NLM Chemicals$$aPapillomavirus E7 Proteins
000298616 650_7 $$2NLM Chemicals$$aE6 protein, Human papillomavirus type 16
000298616 650_2 $$2MeSH$$aHumans
000298616 650_2 $$2MeSH$$aCellular Senescence: physiology
000298616 650_2 $$2MeSH$$aOncogene Proteins, Viral: metabolism
000298616 650_2 $$2MeSH$$aOncogene Proteins, Viral: genetics
000298616 650_2 $$2MeSH$$aUbiquitin-Protein Ligases: metabolism
000298616 650_2 $$2MeSH$$aUbiquitin-Protein Ligases: genetics
000298616 650_2 $$2MeSH$$aTumor Suppressor Protein p53: metabolism
000298616 650_2 $$2MeSH$$aPapillomavirus Infections: virology
000298616 650_2 $$2MeSH$$aPapillomavirus Infections: metabolism
000298616 650_2 $$2MeSH$$aCell Proliferation
000298616 650_2 $$2MeSH$$aRepressor Proteins: metabolism
000298616 650_2 $$2MeSH$$aRepressor Proteins: genetics
000298616 650_2 $$2MeSH$$aPapillomavirus E7 Proteins: metabolism
000298616 650_2 $$2MeSH$$aPapillomavirus E7 Proteins: genetics
000298616 650_2 $$2MeSH$$aCell Line, Tumor
000298616 7001_ $$0P:(DE-He78)0a4c58c6737b30b65df3ed36acc08d4f$$aVelimirović, Milica$$b1$$udkfz
000298616 7001_ $$0P:(DE-He78)c04ec6ab9480d74da506d656185ec7d2$$aBulkescher, Julia$$b2$$udkfz
000298616 7001_ $$aScheffner, Martin$$b3
000298616 7001_ $$0P:(DE-He78)25779f8829ab7a7650e85a4cc871e6ac$$aHoppe-Seyler, Felix$$b4$$eLast author$$udkfz
000298616 7001_ $$0P:(DE-He78)97468f1980416a4376b44e701d25f24b$$aHoppe-Seyler, Karin$$b5$$eLast author$$udkfz
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