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Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation.

Abstract：

:It is believed that Mdm2 suppresses p53 in two ways: transcriptional inhibition by direct binding, and degradation via its E3 ligase activity. To study these functions physiologically, we generated mice bearing a single-residue substitution (C462A) abolishing the E3 function without affecting p53 binding. Unexpectedly, homozygous mutant mice died before E7.5, and deletion of p53 rescued the lethality. Furthermore, reintroducing a switchable p53 by crossing with p53ER(TAM) mice surprisingly demonstrated that the mutant Mdm2(C462A) was rapidly degraded in a manner indistinguishable from that of the wild-type Mdm2. Hence, our data indicate that (1) the Mdm2-p53 physical interaction, without Mdm2-mediated p53 ubiquitination, cannot control p53 activity sufficiently to allow early mouse embryonic development, and (2) Mdm2's E3 function is not required for Mdm2 degradation.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

Itahana K,Mao H,Jin A,Itahana Y,Clegg HV,Lindström MS,Bhat KP,Godfrey VL,Evan GI,Zhang Y

doi

10.1016/j.ccr.2007.09.007

subject

Has Abstract

pub_date

2007-10-01 00:00:00

pages

355-66

issue

4

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(07)00266-8

journal_volume

12

pub_type

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