SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

X. D. Wang, E. Lapi, A. Sullivan, I. Ratnayaka, R. Goldin, R. Hay, X. Lu

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    Abstract

    Oncogene-induced senescence represents a key tumor suppressive mechanism. Here, we show that Ras oncogene-induced senescence can be mediated by the recently identified haploinsufficient tumor suppressor apoptosis-stimulating protein of p53 (ASPP) 2 through a novel and p53/p19(Arf)/p21(waf1/cip1)-independent pathway. ASPP2 suppresses Ras-induced small ubiquitin-like modifier (SUMO)-modified nuclear cyclin D1 and inhibits retinoblastoma protein (Rb) phosphorylation. The lysine residue, K33, of cyclin D1 is a key site for this newly identified regulation. In agreement with the fact that its nuclear localization is required for its oncogenic activity, we show that nuclear cyclin D1 is far more potent than wild-type (WT) cyclin D1 in bypassing Ras-induced senescence. Thus, this study identifies SUMO modification as a positive regulator of nuclear cyclin D1, and reveals a new way by which cell cycle entry and senescence are regulated. Cell Death and Differentiation (2011) 18, 304-314; doi: 10.1038/cdd.2010.101; published online 27 August 2010

    Original languageEnglish
    Pages (from-to)304-314
    Number of pages11
    JournalCell Death & Differentiation
    Volume18
    Issue number2
    DOIs
    Publication statusPublished - Feb 2011

    Keywords

    • ASPP2
    • senescence
    • Ras
    • cyclin D1
    • SUMO
    • APOPTOSIS-STIMULATING PROTEIN
    • ONCOGENIC RAS
    • IN-VIVO
    • TUMOR-SUPPRESSOR
    • BREAST-CANCER
    • B-CELL
    • EXPRESSION
    • P53
    • PHOSPHORYLATION
    • OVEREXPRESSION

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