Document Detail


Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis.
MedLine Citation:
PMID:  19536131     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. Interestingly, MKRN1 used earlier unknown sites, K291 and K292, for p53 ubiquitination and subsequent degradation. Under severe stress conditions, however, MKRN1 primarily induced the efficient degradation of p21. This regulatory process contributed to the acceleration of DNA damage-induced apoptosis by eliminating p21. MKRN1 depletion diminished adriamycin or ultraviolet-induced cell death, whereas ectopic expression of MKRN1 facilitated apoptosis. Furthermore, MKRN1 stable cell lines that constantly produced low levels of p53 and p21 exhibited stabilization of p53, but not p21, with increased cell death on DNA damage. Our results indicate that MKRN1 exhibits dual functions of keeping cells alive by suppressing p53 under normal conditions and stimulating cell death by repressing p21 under stress conditions.
Authors:
Eun-Woo Lee; Min-Sik Lee; Suzanne Camus; Jaewang Ghim; Mi-Ran Yang; Wonkyung Oh; Nam-Chul Ha; David P Lane; Jaewhan Song
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-06-18
Journal Detail:
Title:  The EMBO journal     Volume:  28     ISSN:  1460-2075     ISO Abbreviation:  EMBO J.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-22     Completed Date:  2009-08-04     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  8208664     Medline TA:  EMBO J     Country:  England    
Other Details:
Languages:  eng     Pagination:  2100-13     Citation Subset:  IM    
Affiliation:
Department of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Kyungi-do 440-746, Korea.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis*
Cell Cycle*
DNA Damage
Gene Knockdown Techniques
Humans
Mice
Nerve Tissue Proteins / genetics,  metabolism*
Proteasome Endopeptidase Complex
Ribonucleoproteins / genetics,  metabolism*
Tumor Suppressor Protein p53 / metabolism*
Ubiquitination
rho GTP-Binding Proteins / metabolism*
Chemical
Reg. No./Substance:
0/Makorin ring finger protein 1; 0/Nerve Tissue Proteins; 0/Ribonucleoproteins; 0/Tumor Suppressor Protein p53; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 3.6.5.2/rho GTP-Binding Proteins
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