Author/Authors :
Inuzuka، نويسنده , , Hiroyuki and Tseng، نويسنده , , Alan and Gao، نويسنده , , Daming and Zhai، نويسنده , , Bo and Zhang، نويسنده , , Qing and Shaik، نويسنده , , Shavali and Wan، نويسنده , , Lixin and Ang، نويسنده , , Xiaolu L. and Mock، نويسنده , , Caroline and Yin، نويسنده , , Haoqiang and Stommel، نويسنده , , Jayne M. and Gygi، نويسنده , , Steven and Lahav، نويسنده , , Galit and Asara، نويسنده , , John Q. Xiao، نويسنده , , Zhi-Xiong Jim and Kaelin Jr.، نويسنده , , William G. and Harper، نويسنده , , J. Wade and Wei، نويسنده , , Wenyi، نويسنده ,
Abstract :
Summary
s the major negative regulator of the p53 pathway. Here, we report that Mdm2 is rapidly degraded after DNA damage and that phosphorylation of Mdm2 by casein kinase I (CKI) at multiple sites triggers its interaction with, and subsequent ubiquitination and destruction, by SCFβ-TRCP. Inactivation of either β-TRCP or CKI results in accumulation of Mdm2 and decreased p53 activity, and resistance to apoptosis induced by DNA damaging agents. Moreover, SCFβ-TRCP-dependent Mdm2 turnover also contributes to the control of repeated p53 pulses in response to persistent DNA damage. Our results provide insight into the signaling pathways controlling Mdm2 destruction and further suggest that compromised regulation of Mdm2 results in attenuated p53 activity, thereby facilitating tumor progression.
