Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction

The Mdm2/p53 pathway is compromised in more than 50% of all human cancers, therefore it is an intensive area of research to understand the upstream regulatory pathways governing Mdm2/p53 activity. Mdm2 is frequently overexpressed in human cancers while the molecular mechanisms underlying the timely...

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Main Authors:	Inuzuka, Hiroyuki, Fukushima, Hidefumi, Shaik, Shavali, Wei, Wenyi
Format:	Online
Language:	English
Published:	Impact Journals LLC 2010
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248122/

id	pubmed-3248122
recordtype	oai_dc
spelling	pubmed-32481222012-01-18 Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction Inuzuka, Hiroyuki Fukushima, Hidefumi Shaik, Shavali Wei, Wenyi Research Perspectives The Mdm2/p53 pathway is compromised in more than 50% of all human cancers, therefore it is an intensive area of research to understand the upstream regulatory pathways governing Mdm2/p53 activity. Mdm2 is frequently overexpressed in human cancers while the molecular mechanisms underlying the timely destruction of Mdm2 remain unclear. We recently reported that Casein Kinase I phosphorylates Mdm2 at multiple sites to trigger Mdm2 interaction with, and subsequent ubiquitination and destruction by the SCFβ-TRCP E3 ubiquitin ligase. We also demonstrated that the E3 ligase activity-deficient Mdm2 was still unstable in the G1 phase and could be efficiently degraded by SCFβ-TRCP. Thus our finding expands the current knowledge on how Mdm2 is tightly regulated by both self- and SCFβ-TRCP-dependent ubiquitination to control p53 activity in response to stress. It further indicates that loss of β-TRCP or Casein Kinase I function contributes to elevated Mdm2 expression that is frequently found in various types of tumors. Impact Journals LLC 2010-10-20 /pmc/articles/PMC3248122/ /pubmed/21317463 Text en Copyright: © 2010 Inuzuka et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Inuzuka, Hiroyuki Fukushima, Hidefumi Shaik, Shavali Wei, Wenyi
spellingShingle	Inuzuka, Hiroyuki Fukushima, Hidefumi Shaik, Shavali Wei, Wenyi Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction
author_facet	Inuzuka, Hiroyuki Fukushima, Hidefumi Shaik, Shavali Wei, Wenyi
author_sort	Inuzuka, Hiroyuki
title	Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction
title_short	Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction
title_full	Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction
title_fullStr	Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction
title_full_unstemmed	Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction
title_sort	novel insights into the molecular mechanisms governing mdm2 ubiquitination and destruction
description	The Mdm2/p53 pathway is compromised in more than 50% of all human cancers, therefore it is an intensive area of research to understand the upstream regulatory pathways governing Mdm2/p53 activity. Mdm2 is frequently overexpressed in human cancers while the molecular mechanisms underlying the timely destruction of Mdm2 remain unclear. We recently reported that Casein Kinase I phosphorylates Mdm2 at multiple sites to trigger Mdm2 interaction with, and subsequent ubiquitination and destruction by the SCFβ-TRCP E3 ubiquitin ligase. We also demonstrated that the E3 ligase activity-deficient Mdm2 was still unstable in the G1 phase and could be efficiently degraded by SCFβ-TRCP. Thus our finding expands the current knowledge on how Mdm2 is tightly regulated by both self- and SCFβ-TRCP-dependent ubiquitination to control p53 activity in response to stress. It further indicates that loss of β-TRCP or Casein Kinase I function contributes to elevated Mdm2 expression that is frequently found in various types of tumors.
publisher	Impact Journals LLC
publishDate	2010
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248122/
_version_	1611497259147460608

Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction

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