年間 6 号発行
ISSN 印刷: 1045-4403
ISSN オンライン: 2162-6502
Indexed in
Regulation of the p53 Tumor Suppressor Pathway: The Problems and Promises of Studying Mdm2's E3 Ligase Function
要約
Mdm2 is a major negative regulator of the tumor suppressor p53 and has long been thought to inhibit p53 in two ways: by ubiquitinating p53 to signal for its degradation, and by binding to p53, masking its transactivation domain. Mdm2 is also believed to control its own levels by autoubiquitination. Despite the widespread acceptance of these hypotheses, the supporting data were drawn primarily from in vitro and ectopic expression studies, which have not always been corroborated when tested in the more physiologically relevant setting of a knock-in or knock-out mouse model. Recently, a mouse model was generated in which a single point mutation (C462A) in Mdm2’s RING domain abrogated Mdm2’s E3 activity while leaving Mdm2-p53 binding intact. This study called into question two major dogmas about Mdm2 by suggesting that when endogenously expressed, (1) Mdm2 cannot inhibit p53 sufficiently by binding without ubiquitination, and (2) Mdm2 may not be regulated by autoubiquitination. Two years later, we are still without definitive answers for why these results conflict with previous findings, but we have gained new insights from subsequent studies. Here, we discuss potential reasons for the discrepancies concerning Mdm2’s functions and how they might be resolved, taking into account new research in the field.
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