Document Detail

Methylation of RASSF1A gene promoter is regulated by p53 and DAXX.
MedLine Citation:
PMID:  23038753     Owner:  NLM     Status:  MEDLINE    
Inactivation of the tumor suppressor Ras-association domain family 1 isoform A (RASSF1A) due to epigenetic silencing occurs in a variety of human cancers, and still largely unknown are the regulators and mechanisms underlying RASSF1A gene promoter methylation. Herein, we report that this methylation is regulated by p53 and death-associated protein 6 (DAXX) in acute lymphoblastic leukemia (ALL). We found that p53 bound to the RASSF1A promoter, recruiting DAXX as well as DNA methyltransferase 1 (DNMT1) for DNA methylation, which subsequently resulted in inactivation of RASSF1A in wild-type p53 ALL cells. Although the presence of p53 was required for the recruitment of DAXX and DNMT1 to the RASSF1A promoter, fluctuation in p53 protein levels did not affect the rates of RASSF1A methylation. Conversely, methylation of RASSF1A promoter was critically controlled by DAXX, as the enforced overexpression of DAXX led to enhanced RASSF1A promoter methylation, whereas inhibition of DAXX reduced RASSF1A methylation. Interestingly, we found that the p53/DAXX-mediated RASSF1A methylation regulated murine double minute 2 (MDM2) protein stability in ALL. Our results reveal a novel function for p53 in the methylation of RASSF1A promoter by its interaction with DAXX. Discovery of this mechanism provides new insight into the interactions among the tumor-related factors p53, RASSF1A, DAXX, and MDM2 in cancer pathogenesis.
Hailong Zhang; Jing He; Jiansha Li; Dan Tian; Lubing Gu; Muxiang Zhou
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-04
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  27     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-03-07     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  232-42     Citation Subset:  IM    
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MeSH Terms
Adaptor Proteins, Signal Transducing / physiology*
Base Sequence
Cell Line, Tumor
DNA Methylation*
DNA Primers
Molecular Sequence Data
Nuclear Proteins / physiology*
Polymerase Chain Reaction
Promoter Regions, Genetic*
Tumor Suppressor Protein p53 / physiology*
Tumor Suppressor Proteins / genetics*
Grant Support
R01 CA123490/CA/NCI NIH HHS; R01 CA123490/CA/NCI NIH HHS; R01 CA143107/CA/NCI NIH HHS; R01 CA143107/CA/NCI NIH HHS
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/DAXX protein, human; 0/DNA Primers; 0/Nuclear Proteins; 0/RASSF1 protein, human; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; 9007-49-2/DNA

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