Cellular senescence has been recently shown to have an important role in 
opposing tumour initiation and promotion. Senescence induced by oncogenes or by 
loss of tumour suppressor genes is thought to critically depend on induction of 
the p19(Arf)-p53 pathway. The Skp2 E3-ubiquitin ligase can act as a 
proto-oncogene and its aberrant overexpression is frequently observed in human 
cancers. Here we show that although Skp2 inactivation on its own does not induce 
cellular senescence, aberrant proto-oncogenic signals as well as inactivation of 
tumour suppressor genes do trigger a potent, tumour-suppressive senescence 
response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and 
oncogenic-stress-driven senescence neither elicit activation of the p19(Arf)-p53 
pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further 
demonstrate that genetic Skp2 inactivation evokes cellular senescence even in 
oncogenic conditions in which the p19(Arf)-p53 response is impaired, whereas a 
Skp2-SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient 
cells and tumour regression in preclinical studies. Our findings therefore 
provide proof-of-principle evidence that pharmacological inhibition of Skp2 may 
represent a general approach for cancer prevention and therapy.