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@ARTICLE{Avenhaus:298616,
      author       = {A. Avenhaus$^*$ and M. Velimirović$^*$ and J.
                      Bulkescher$^*$ and M. Scheffner and F. Hoppe-Seyler$^*$ and
                      K. Hoppe-Seyler$^*$},
      title        = {{E}6{AP} is essential for the proliferation of
                      {HPV}-positive cancer cells by preventing senescence.},
      journal      = {PLoS pathogens},
      volume       = {21},
      number       = {2},
      issn         = {1553-7366},
      address      = {Lawrence, Kan.},
      publisher    = {PLoS},
      reportid     = {DKFZ-2025-00316},
      pages        = {e1012914 -},
      year         = {2025},
      note         = {#EA:D365#LA:D365#},
      abstract     = {Oncogenic 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.},
      keywords     = {Humans / Cellular Senescence: physiology / Oncogene
                      Proteins, Viral: metabolism / Oncogene Proteins, Viral:
                      genetics / Ubiquitin-Protein Ligases: metabolism /
                      Ubiquitin-Protein Ligases: genetics / Tumor Suppressor
                      Protein p53: metabolism / Papillomavirus Infections:
                      virology / Papillomavirus Infections: metabolism / Cell
                      Proliferation / Repressor Proteins: metabolism / Repressor
                      Proteins: genetics / Papillomavirus E7 Proteins: metabolism
                      / Papillomavirus E7 Proteins: genetics / Cell Line, Tumor /
                      Oncogene Proteins, Viral (NLM Chemicals) / Ubiquitin-Protein
                      Ligases (NLM Chemicals) / UBE3A protein, human (NLM
                      Chemicals) / Tumor Suppressor Protein p53 (NLM Chemicals) /
                      Repressor Proteins (NLM Chemicals) / Papillomavirus E7
                      Proteins (NLM Chemicals) / E6 protein, Human papillomavirus
                      type 16 (NLM Chemicals)},
      cin          = {D365},
      ddc          = {610},
      cid          = {I:(DE-He78)D365-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39919145},
      pmc          = {pmc:PMC11805377},
      doi          = {10.1371/journal.ppat.1012914},
      url          = {https://inrepo02.dkfz.de/record/298616},
}