論文

査読有り
2013年5月

A Network of Substrates of the E3 Ubiquitin Ligases MDM2 and HUWE1 Control Apoptosis Independently of p53

SCIENCE SIGNALING
  • Manabu Kurokawa
  • ,
  • Jiyeon Kim
  • ,
  • Joseph Geradts
  • ,
  • Kenkyo Matsuura
  • ,
  • Liu Liu
  • ,
  • Xu Ran
  • ,
  • Wenle Xia
  • ,
  • Thomas J. Ribar
  • ,
  • Ricardo Henao
  • ,
  • Mark W. Dewhirst
  • ,
  • Wun-Jae Kim
  • ,
  • Joseph E. Lucas
  • ,
  • Shaomeng Wang
  • ,
  • Neil L. Spector
  • ,
  • Sally Kornbluth

6
274
開始ページ
ra32
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1126/scisignal.2003741
出版者・発行元
AMER ASSOC ADVANCEMENT SCIENCE

In the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. HUWE1 ubiquitylates the antiapoptotic factor Mcl-1, and we found that HUWE1 also ubiquitylated PP5 (protein phosphatase 5), which indirectly inhibited apoptosome activation. Breast cancers that are positive for the tyrosine receptor kinase HER2 (human epidermal growth factor receptor 2) tend to be highly aggressive. In HER2-positive breast cancer cells treated with the HER2 tyrosine kinase inhibitor lapatinib, MDM2 was degraded and HUWE1 was stabilized. In contrast, in breast cancer cells that acquired resistance to lapatinib, the abundance of MDM2 was not decreased and HUWE1 was degraded, which inhibited apoptosis, regardless of p53 status. MDM2 inhibition overcame lapatinib resistance in cells with either wild-type or mutant p53 and in xenograft models. These findings demonstrate broader, p53-independent roles for MDM2 and HUWE1 in apoptosis and specifically suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance.

Web of Science ® 被引用回数 : 41

リンク情報
DOI
https://doi.org/10.1126/scisignal.2003741
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/23652204
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770270
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000318691600002&DestApp=WOS_CPL
URL
http://europepmc.org/abstract/med/23652204
URL
http://orcid.org/0000-0003-4612-6031
ID情報
  • DOI : 10.1126/scisignal.2003741
  • ISSN : 1945-0877
  • ORCIDのPut Code : 45669882
  • PubMed ID : 23652204
  • PubMed Central 記事ID : PMC3770270
  • Web of Science ID : WOS:000318691600002

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