ASPP2 mediates senescence and inhibits autophagy and tumourgenicity induced by H-RasV12


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Xin Lu

Ludwig Institute for Cancer Research, University of Oxford, UK

Abstract

ASPP2 mediates senescence and inhibits autophagy and tumourgenicity induced by H-RasV12

ASPP2 can stimulate the apoptotic function of the p53 family in vivo. Furthermore, the role of ASPP2 as a bone fide tumour suppressor has recently been demonstrated in mice. We now have evidence that ASPP2 can inhibit the tumourigenic function of H-RasV12 by mediating Ras induced senescence through a novel pathway. ASPP2 colocalizes with Ras at the cell membrane and acts as an amplifier of the Ras/MAPK and Ras/PI3K/AKT pathways. As a result, ASPP2 mediates senescence by preventing H-RasV12 from inducing autophagy, a biological process known to suppress aging. The N-terminus of ASPP2, a region that binds Ras but not p53, is required and sufficient for ASPP2 to activate Ras signalling, to mediate senescence and to inhibit autophagy and tumourigenicity induced by H-RasV12. This novel function of ASPP2 has established an inverse correlation between autophagy and senescence induced by H-RasV12 and may form a basis for future therapy.