Hypoxia activates tumor suppressor p53 by inducing ATR-Chk1 kinase cascade-mediated phosphorylation and consequent 14-3-3γ inactivation of MDMX protein.

The Journal of Biological Chemistry
Jun-Ho LeeHua Lu

Abstract

It has been known that p53 can be induced and activated by hypoxia, an abnormal condition that often occurs in rapidly growing solid tumors or when normal tissues undergo ischemia. Although the ATR-Chk1 kinase cascade was associated with hypoxia-induced p53 activation, molecules that directly link this hypoxia-ATR-Chk1 pathway to p53 activation have been elusive. Here, we showed that hypoxia could induce phosphorylation of MDMX at Ser-367 and enhance the binding of this phosphorylated MDMX to 14-3-3γ, consequently leading to p53 activation. A Chk1 inhibitor or knockdown of ATR and Chk1 inhibited the phosphorylation of MDMX at Ser-367 and impaired the binding of MDMX to 14-3-3γ in addition to p53 activation in response to hypoxia. In primary mouse embryonic fibroblast cells that harbor a mutant MDMX, including the S367A mutation, hypoxia also failed to induce the binding of this mutant MDMX to 14-3-3γ and to activate p53 and its direct targets. These results demonstrate that hypoxia can activate p53 through inactivation of MDMX by the ATR-Chk1-MDMX-14-3-3γ pathway.

References

Jul 1, 1993·Molecular and Cellular Biology·J ChenA J Levine
Jul 1, 1993·Genes & Development·X WuA J Levine
Feb 7, 1998·Genes & Development·J D SilicianoM B Kastan
May 5, 1998·Molecular and Cellular Biology·C SchmaltzD E Fisher
Jun 20, 1998·The Journal of Biological Chemistry·M V BlagosklonnyL Neckers
Apr 17, 1999·Molecular and Cellular Biology·X ZengH Lu
Dec 23, 1999·The Journal of Biological Chemistry·D A SharpD L George
Oct 18, 2000·Proceedings of the National Academy of Sciences of the United States of America·C ChaoY Xu
Oct 19, 2001·EMBO Reports·R StadA G Jochemsen
Feb 28, 2002·Molecular and Cellular Biology·Ester M HammondAmato J Giaccia
Jul 9, 2002·Molecular and Cellular Biology·Domenico MiglioriniJean-Christophe Marine
Sep 24, 2002·The Journal of Biological Chemistry·Baoguang ZhaoBin-Bing S Zhou
Jan 10, 2003·The Journal of Biological Chemistry·Ester M HammondAmato J Giaccia
Jul 16, 2004·Cell Cycle·Jean-Christophe Marine, Aart G Jochemsen
Jul 29, 2004·DNA Repair·Ester M Hammond, Amato J Giaccia
Aug 17, 2004·The Journal of Biological Chemistry·Mu-Shui Dai, Hua Lu
Aug 18, 2004·Genes & Development·Paul R AndreassenToshiyasu Taniguchi
Sep 18, 2004·Cancer Research·Ester M HammondAmato J Giaccia
Oct 9, 2004·The Journal of Biological Chemistry·Thelma ThompsonLyubomir T Vassilev
May 4, 2005·Biochemical and Biophysical Research Communications·Ester M Hammond, Amato J Giaccia
Aug 9, 2005·Cancer Letters·Ester M HammondAmato J Giaccia
Mar 3, 2006·The EMBO Journal·Cynthia LeBronJiandong Chen
Sep 1, 2006·Molecular and Cellular Biology·Yaron PeregAart G Jochemsen
Dec 13, 2006·The EMBO Journal·Stjepan UldrijanKaren H Vousden
Jul 10, 2007·Cancer Research·Hidehiko KawaiZhi-Min Yuan
May 3, 2008·Genes & Development·Xiaohong H YangLee Zou
Sep 2, 2009·Current Genomics·F ManciniF Moretti
Feb 23, 2010·Trends in Cell Biology·Mark WadeGeoffrey M Wahl
Jul 7, 2011·Proceedings of the National Academy of Sciences of the United States of America·Vinod PantGuillermina Lozano
Jul 7, 2011·Proceedings of the National Academy of Sciences of the United States of America·Lei HuangZhi-Min Yuan

❮ Previous
Next ❯

Citations

May 12, 2015·The Journal of Clinical Investigation·Katarzyna B LeszczynskaEster M Hammond
May 12, 2015·The Journal of Clinical Investigation·Zhong Yun, Peter M Glazer
May 10, 2015·DNA Repair·Susan E Scanlon, Peter M Glazer
May 26, 2015·DNA Repair·Isabella Marcomini, Susan M Gasser
Dec 4, 2014·International Journal of Molecular Sciences·Qian Hao, William C Cho
Jun 23, 2018·EMBO Molecular Medicine·Daniel E FoxlerTyson V Sharp
Jan 8, 2021·Cancers·Airelle LahalleLaurent Le Cam

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Ataxia telangiectasia

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.

Ataxia telangiectasia (MDS)

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.

Related Papers

Molecular and Cellular Biology
Daniele M GilkesJiandong Chen
The Journal of Biological Chemistry
David L WaningLindsey D Mayo
© 2021 Meta ULC. All rights reserved