Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase.
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.
Inuzuka
Hiroyuki
H
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Tseng
Alan
A
Gao
Daming
D
Zhai
Bo
B
Zhang
Qing
Q
Shaik
Shavali
S
Wan
Lixin
L
Ang
Xiaolu L
XL
Mock
Caroline
C
Yin
Haoqiang
H
Stommel
Jayne M
JM
Gygi
Steven
S
Lahav
Galit
G
Asara
John
J
Xiao
Zhi-Xiong Jim
ZX
Kaelin
William G
WG
Harper
J Wade
JW
Wei
Wenyi
W
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*
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