Document Detail


The antiapoptotic DeltaNp73 is degraded in a c-Jun-dependent manner upon genotoxic stress through the antizyme-mediated pathway.
MedLine Citation:
PMID:  20185758     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
p73, the structural and functional homologue of p53, exists as two major forms: the transactivation-proficient, proapoptotic TAp73 or the transactivation-deficient, antiapoptotic DNp73. Expectedly, expression of both these major forms has to be coordinated precisely to achieve the desired cellular outcome. Genotoxic insults resulting in cell death lead to the stabilization of TAp73, mainly through posttranslational modifications, and the concomitant degradation of DNp73, through poorly understood mechanisms. We have therefore investigated the possible mechanisms of stress-induced DNp73 degradation and show here that c-Jun, the AP-1 family member activated by stress signals and involved in stabilizing TAp73, promotes DNp73 degradation. Genotoxic stress-mediated DNp73 degradation was found to occur in a c-Jun-dependent manner through a ubiquitin-independent but proteasome-dependent mechanism. Absence or down-regulation of c-Jun expression abrogated the reduction of DNp73 levels upon stress insults, whereas overexpression of c-Jun led to its degradation. c-Jun controlled DNp73 degradation through the nonclassical, polyamine-induced antizyme (Az) pathway by regulating the latter's processing during stress response. Consistently, expression of c-Jun or Az, or addition of polyamines, promoted DNp73 degradation, whereas silencing Az expression or inhibiting Az activity in cells exposed to stress reduced c-Jun-dependent DNp73 degradation. Moreover, Az was able to bind to DNp73. These data together demonstrate the existence of a c-Jun-dependent mechanism regulating the abundance of the antiapoptotic DNp73 in response to genotoxic stress.
Authors:
Iqbal Dulloo; Ganesan Gopalan; Gerry Melino; Kanaga Sabapathy
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-02-25
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-22     Completed Date:  2010-04-22     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4902-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis*
Cell Line
DNA Damage*
DNA-Binding Proteins / metabolism*
Humans
Mice
Nuclear Proteins / metabolism*
Proteasome Endopeptidase Complex / metabolism
Protein Processing, Post-Translational*
Proteins / metabolism*
Proto-Oncogene Proteins c-jun / metabolism*
Signal Transduction*
Tumor Suppressor Proteins / metabolism*
Ubiquitin / metabolism
Ubiquitination
Grant Support
ID/Acronym/Agency:
MC_U132670600//Medical Research Council
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Nuclear Proteins; 0/Proteins; 0/Proto-Oncogene Proteins c-jun; 0/Tumor Suppressor Proteins; 0/Ubiquitin; 0/ornithine decarboxylase antizyme; 0/tumor suppressor protein p73; EC 3.4.25.1/Proteasome Endopeptidase Complex
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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