title: An indirect role for ASPP1 in limiting p53-dependent p21 expression and cellular senescence.
abstract: In addition to acting as a transcriptional cofactor for p53, ASPP1 has been shown to function in the cytoplasm to regulate the nuclear localization and activity of YAP/TAZ. We show here that the ability of ASPP1 to activate YAP results in the decreased expression of LATS2, which lowers the ability of p53 to induce p21, cell-cycle arrest and senescence. ASPP1 expression peaks in S-phase, and down-regulation of ASPP1 leads to a reduction in DNA synthesis and enhanced senescence in response to drugs that impede DNA replication. These activities of cytoplasmic ASPP1 in opposing p53-mediated p21 expression are in contrast to the role of nuclear ASPP1 in cooperating with p53 to induce the expression of apoptotic target genes, and may help to dampen p53 activity in normal cells.
authors: The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK.
authors: Arnaud M
authors: AM
authors: Vigneron
authors: Karen H
authors: KH
authors: Vousden
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000230:Adenocarcinoma / Q000473:pathology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D003110:Colonic Neoplasms / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology; D003609:Dactinomycin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D009687:Nuclear Proteins / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C498406:PPP1R13B protein, human; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C456659:YY1AP1 protein, human; D003609:Dactinomycin; D004317:Doxorubicin; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D006918:Hydroxyurea