Abstract
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 p73beta is introduced into cultured hepatoma cells that express AFP. Transient co-transfection of p53 family members showed that p53 and transactivating (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. Chromatin immunoprecipitation 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 wild type liver, with increased binding of TA-p73 to chromatin in the absence of p53. Sequential chromatin immunoprecipitation analyses revealed that TA-p73 and p53 bind simultaneously to their shared regulatory site in wild type liver. Like the founding family member p53, TA-p73 represses AFP expression by chromatin structure alteration, targeting reduction of acetylated histone H3 lysine 9 and increased dimethylated histone H3 lysine 9 levels. However, chromatin-bound TA-p73 is associated with elevated di- and tri-methylated histone H3 lysine 4 levels in p53-null liver and hepatoma cells, concomitant with a reduced ability to repress transcription compared with p53.
Highlights
The truncated N termini of the ⌬N isoforms, of p63 and p73 [1]
Aberrant expression of the ␣-fetoprotein (AFP) Gene Expression Is Repressed by Expression of p73—Transcription of p63 and p73 from upstream or downstream promoters generates protein variants with extended N termini, containing TA domains or N-terminal deleted forms (⌬N) that may interact with TA isoforms to alter their function or display their own regulatory effects [1, 2, 9]
The ability to activate p21 in other cell types has been previously shown for transactivating isoforms of p63 and p73 [30, 31]. We find that both p63␣ and ␥ activated transcription of endogenous p21 in mouse and human hepatoma cells, as did p73 (Fig. 1, B and D)
Summary
The truncated N termini of the ⌬N isoforms, of p63 and p73 [1]. The TA isoforms of p63/p73 activate the transcription of specific, p53-regulated genes with functions in cell cycle arrest and apoptosis, as well as regulate other genes in a p53-independent manner. AFP Gene Expression Is Repressed by Expression of p73—Transcription of p63 and p73 from upstream or downstream promoters generates protein variants with extended N termini, containing TA domains or N-terminal deleted forms (⌬N) that may interact with TA isoforms to alter their function or display their own regulatory effects [1, 2, 9].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
