SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

Xin Lu (1) , Xiaodan Wang (1) , Eleonora Lapi (1) , Alexandra Sullivan (1) , Indrika Ratnayaka (1) , Robert Goldin (1) , Ronald Hay (1)

1 Nuffield Department of Clinical Medicine [Oxford]

Oncogene-induced senescence represents a key tumour suppressive mechanism. Here we show that Ras oncogene-induced senescence can be mediated by the recently identified haploinsufficent tumour suppressor ASPP2 through a novel and p53/p19Arf/p21waf1/cip1-independent pathway. ASPP2 suppresses Ras-induced SUMO-modified nuclear cyclin D1 and inhibits 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 localisation is required for its oncogenic activity, we show that nuclear cyclin D1 is far more potent than wild type 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.

Mots clés: ASPP2; senescence; Ras; Cyclin D1; SUMO

Xin Lu, Xiaodan Wang, Eleonora Lapi, Alexandra Sullivan, Indrika Ratnayaka, et al.. SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.101⟩. ⟨hal-00570132⟩