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Papers In Press, published online ahead of print October 2, 2005
Department of Biochemistry and Molecular Biology, University of Texas, Houston, TX 77030
Corresponding Author: mbarton{at}odin.mdacc.tmc.edu
Aberrant expression of the alpha-fetoprotein (AFP) gene is a diagnostic, tumor marker of hepatocellular carcinoma. We find that AFP gene expression is repressed by the TP53 family member p73 during normal hepatic development and when p73alpha or p73ß is introduced into cultured hepatoma cells, which express AFP. Transient co-transfection of p53 family members showed that p53 and TA-p73, but not TA-p63, repress endogenous AFP transcription additively or independently. p53-independent functions of p73 are further supported by delayed, p73-associated compensation of AFP repression during development of the p53-null mouse. ChIP assays of normal and p53-null mouse liver tissue showed that TA-p73 binds at a previously identified, p53-repressor site (-860/-830) within the distal promoter of AFP at a level equivalent to p53 in WT liver, with increased binding of TA-p73 to chromatin in the absence of p53. Re-ChIP analyses revealed that TA-p73 and p53 bind simultaneously to their shared regulatory site in WT liver. Like the founding family member p53, TA-p73 represses AFP expression by chromatin structure alteration, targeting reduction of AcH3K9 and increased diMetH3K9 levels. However, chromatin-bound TA-p73 is associated with elevated di- and tri-MetH3K4 levels in p53-null liver and hepatoma cells, concomitant with a reduced ability to repress transcription compared to p53.
J. Biol. Chem, 10.1074/jbc.M504655200
Submitted on April 28, 2005
Revised on September 28, 2005
Accepted on October 2, 2005
Family members p53 and p73 act together in chromatin modification and direct repression of AFP transcription
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