downregulation of vrk1 by p53 in response to dna damage is mediated by the autophagic pathwaydownregulation vrk1的p53在应对dna损伤介导的自噬途径.pdfVIP

Downregulation of VRK1 by p53 in Response to DNA Damage Is Mediated by the Autophagic Pathway 1 ´ 2 1 Alberto Valbuena , Susana Castro-Obregon , Pedro A. Lazo * ´ ´ ´ 1 Experimental Therapeutics and Translational Oncology Program, Instituto de Biologıa Molecular y Celular del Cancer, Consejo Superior de Investigaciones Cientıficas ´ (CSIC) - Universidad de Salamanca, Salamanca, Spain, 2 Department of Developmental Genetics and Molecular Physiology, Instituto de Biotecnologıa, Universidad ´ ´ ´ Nacional Autonoma de Mexico, Cuernavaca, Morelos, Mexico Abstract Human VRK1 induces a stabilization and accumulation of p53 by specific phosphorylation in Thr18. This p53 accumulation is reversed by its downregulation mediated by Hdm2, requiring a dephosphorylated p53 and therefore also needs the removal of VRK1 as stabilizer. This process requires export of VRK1 to the cytosol and is inhibited by leptomycin B. We have identified that downregulation of VRK1 protein levels requires DRAM expression, a p53-induced gene. DRAM is located in the endosomal-lysosomal compartment. Induction of DNA damage by UV, IR, etoposide and doxorubicin stabilizes p53 and induces DRAM expression, followed by VRK1 downregulation and a reduction in p53 Thr18 phosphorylation. DRAM expression is induced by wild-type p53, but not by common human