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dNTP metabolism links mechanical cues and YAP/TAZ to cell growth and oncogene‐induced senescence
Authors:Giulia Santinon  Irene Brian  Arianna Pocaterra  Patrizia Romani  Elisa Franzolin  Chiara Rampazzo  Silvio Bicciato  Sirio Dupont
Affiliation:1. Department of Molecular Medicine, University of Padova, Padova, Italy;2. Department of Biology, University of Padova, Padova, Italy;3. Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
Abstract:YAP/TAZ, downstream transducers of the Hippo pathway, are powerful regulators of cancer growth. How these factors control proliferation remains poorly defined. Here, we found that YAP/TAZ directly regulate expression of key enzymes involved in deoxynucleotide biosynthesis and maintain dNTP precursor pools in human cancer cells. Regulation of deoxynucleotide metabolism is required for YAP‐induced cell growth and underlies the resistance of YAP‐addicted cells to chemotherapeutics targeting dNTP synthesis. During RAS‐induced senescence, YAP/TAZ bypass RAS‐mediated inhibition of nucleotide metabolism and control senescence. Endogenous YAP/TAZ targets and signatures are inhibited by RAS/MEK1 during senescence, and depletion of YAP/TAZ is sufficient to cause senescence‐associated phenotypes, suggesting a role for YAP/TAZ in suppression of senescence. Finally, mechanical cues, such as ECM stiffness and cell geometry, regulate senescence in a YAP‐dependent manner. This study indicates that YAP/TAZ couples cell proliferation with a metabolism suited for DNA replication and facilitates escape from oncogene‐induced senescence. We speculate that this activity might be relevant during the initial phases of tumour progression or during experimental stem cell reprogramming induced by YAP.
Keywords:mechanotransduction  nucleotide metabolism  oncogene‐induced senescence  YAP/TAZ
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