An 11S proteasome regulatory pathway controls anticancer sensitivity in p53-deficient tumor cells

【摘要】：Ubiquitin-independent protein degradation is an emerging new field in proteasome-mediated protein decay.The proteasome activator,REG,is a major player mediating the ubiquitin-independent degradation of proteins including numerous tumor suppressors.Overexpressed in many human cancers,REG promotes cancer progression in animal models.How this REGproteasome pathway is regulated,particularly for the control of p21/CIP in p53 defective cancer cells during cell cycle or genotoxic insults,remains unclear.Here we show that NIP30,a novel REGγ regulator,inhibits REG activity,attenuates cell growth,and sensitizes p53-compromised cells to chemotherapeutic agents.The inhibitory role of NIP30 requires tight binding to REG via an evolutionarily conserved serine-rich domain with phosphorylation at 4 specific serine sites.We find the cyclindependent phosphatase,CDC25 A,regulates phosphorylation of NIP30,required for binding to REG,and therefore the REGdependent degradation of p21/CIP during the cell cycle or DNA damage response.Regulation of p21 in vivo by the CDC25 ANIP30-REG pathway was validated in p53-/-and p53/REG double-deficient mice.Peptide phospho-NIP30 mimetics significantly enhance the growth inhibitory effect of anti-cancer drugs in vitro and in vivo.Our results provide insights into the regulatory signaling that controls the ubiquitin-independent REG-proteasome system in modulating carcinogenesis.Understanding this avenue of regulation of p53-independent cell growth may allow a promising approach in cancer therapy.