Escoll M, Gargini R, Cuadrado A, Anton I M, Wandosell F
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.
Oncogene. 2017 Jun 22;36(25):3515-3527. doi: 10.1038/onc.2016.518. Epub 2017 Feb 6.
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.
野生型p53（wtp53）被描述为一种肿瘤抑制基因；该基因的突变发生在许多人类癌症中，并促进致癌能力。在此，我们证实突变型p53（mtp53）的致癌活性是由WASP相互作用蛋白（WIP）驱动的。从表达mtp53的胶质母细胞瘤和乳腺癌细胞（BCC）中敲低WIP，可显著降低癌症干细胞（CSC）样细胞的增殖和生长能力，并降低CSC样标志物（CD133、CD44或YAP/TAZ）的表达。在人星形胶质细胞中过表达mtp53可增强其在悬浮培养中的增殖能力，并增加CSC标志物和WIP的表达。敲低WIP会损害体内胶质母细胞瘤和BCC肿瘤的生长能力。我们发现WIP被AKT2磷酸化，并通过增强PI3K/AKT2介导的整合素/受体循环途径受到mtp53/p63的调控。WIP通过控制YAP/TAZ的稳定性来调节这一致癌途径。因此，我们在mtp53下游建立了一条新的CSC信号通路，其中AKT2调节WIP并控制YAP/TAZ的稳定性。
