title: Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase.
abstract: Mdm2 is 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 SCF(beta-TRCP). Inactivation of either beta-TRCP or CKI results in accumulation of Mdm2 and decreased p53 activity, and resistance to apoptosis induced by DNA damaging agents. Moreover, SCF(beta-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.
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors: Hiroyuki
authors: H
authors: Inuzuka
authors: Alan
authors: A
authors: Tseng
authors: Daming
authors: D
authors: Gao
authors: Bo
authors: B
authors: Zhai
authors: Qing
authors: Q
authors: Zhang
authors: Shavali
authors: S
authors: Shaik
authors: Lixin
authors: L
authors: Wan
authors: Xiaolu L
authors: XL
authors: Ang
authors: Caroline
authors: C
authors: Mock
authors: Haoqiang
authors: H
authors: Yin
authors: Jayne M
authors: JM
authors: Stommel
authors: Steven
authors: S
authors: Gygi
authors: Galit
authors: G
authors: Lahav
authors: John
authors: J
authors: Asara
authors: Zhi-Xiong Jim
authors: ZX
authors: Xiao
authors: William G
authors: WG
authors: Kaelin
authors: J Wade
authors: JW
authors: Harper
authors: Wenyi
authors: W
authors: Wei
mesh_terms: D000818:Animals; D001483:Base Sequence; D047389:Casein Kinase I / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D034741:RNA, Small Interfering; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C471644:BTRC protein, human; D034741:RNA, Small Interfering; D044844:beta-Transducin Repeat-Containing Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D047389:Casein Kinase I