Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ.
Wild-type p53 (wtp53) is described as a tumour suppressor gene; mutations in this gene occur in many human cancers and promote oncogenic capacity. Here, we establish that the oncogenic activity of mutant p53 (mtp53) is driven by the WASP-interacting protein (WIP). WIP knockdown from mtp53-expressing glioblastoma and breast cancer cells (BCC) greatly reduced proliferation and growth capacity of cancer stem cell (CSC)-like cells and decreased CSC-like markers (CD133, CD44 or YAP/TAZ). mtp53 overexpression in human astrocytes enhanced their proliferative capacity in suspension culture and increased expression of CSC markers and WIP. WIP knockdown compromised tumour glioblastoma and BCC growth capacity in vivo. We show that WIP is phosphorylated by AKT2 and is regulated by mtp53/p63 through enhancement of PI3K/AKT2-mediated integrin/receptor recycling pathways. WIP regulates this oncogenic pathway by controlling YAP/TAZ stability. We thus establish a new CSC signalling pathway downstream of mtp53 in which AKT2 regulates WIP and controls YAP/TAZ stability.
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, Madrid, Spain.
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Escoll
Centro Nacional de Biotecnología (CNB-CSIC), Department of Molecular and Cellular Biology, Darwin 3, Madrid, Spain.
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Gargini
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, Madrid, Spain.|Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Instituto de Investigación Sanitaria La Paz (IdiPaz) and Universidad Autónoma Madrid, Madrid, Spain.
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Cuadrado
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, Madrid, Spain.|Centro Nacional de Biotecnología (CNB-CSIC), Department of Molecular and Cellular Biology, Darwin 3, Madrid, Spain.
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Anton
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, Madrid, Spain.
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Wandosell
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C495901:TP53 protein, human; C115051:TP63 protein, human; C109903:WIPF1 protein, human; C088374:YAP1 protein, human; C108675:TAFAZZIN protein, human; C494921:AKT2 protein, human