Direct activation of forkhead box O3 by tumor suppressors p53 and p73 is disrupted during liver regeneration in mice

Authors


  • Potential conflict of interest: Nothing to report.

  • This work was supported by funds from the National Institutes of Health (grant DK078024 to Michelle Craig Barton, grant AG028865 to Gretchen J. Darlington, and grant P30 DK056338 to the Functional Genomics Core of the Texas Medical Center Digestive Disease Center) and in part by a Cancer Center Support Grant from the National Cancer Institute to the University of Texas M.D. Anderson Cancer Center. Svitlana Kurinna received support from the William Randolph Hearst Foundation and a Sylvan Rodriguez Scholarship from the Cancer Answers Foundation

Abstract

The p53 family of proteins regulates the expression of target genes that promote cell cycle arrest and apoptosis, which may be linked to cellular growth control as well as tumor suppression. Within the p53 family, p53 and the transactivating p73 isoform (TA-p73) have hepatic-specific functions in development and tumor suppression. Here, we determined TA-p73 interactions with chromatin in the adult mouse liver and found forkhead box O3 (Foxo3) to be one of 158 gene targets. Global profiling of hepatic gene expression in the regenerating liver versus the quiescent liver revealed specific, functional categories of genes regulated over the time of regeneration. Foxo3 is the most responsive gene among transcription factors with altered expression during regenerative cellular proliferation. p53 and TA-p73 bind a Foxo3 p53 response element (p53RE) and maintain active expression in the quiescent liver. During regeneration of the liver, the binding of p53 and TA-p73, the recruitment of acetyltransferase p300, and the active chromatin structure of Foxo3 are disrupted along with a loss of Foxo3 expression. In agreement with the loss of Foxo3 transcriptional activation, a decrease in histone activation marks (dimethylated histone H3 at lysine 4, acetylated histone H3 at lysine 14, and acetylated H4) at the Foxo3 p53RE was detected after partial hepatectomy in mice. These parameters of Foxo3 regulation are reestablished with the completion of liver growth and regeneration and support a temporary suspension of p53 and TA-p73 regulatory functions in normal cells during tissue regeneration. p53-dependent and TA-p73–dependent activation of Foxo3 was also observed in mouse embryonic fibroblasts and in mouse hepatoma cells overexpressing p53, TA-p73α, and TA-p73β isoforms. Conclusion: p53 and p73 directly bind and activate the expression of the Foxo3 gene in the adult mouse liver and murine cell lines. p53, TA-p73, and p300 binding and Foxo3 expression decrease during liver regeneration, and this suggests a critical growth control mechanism mediated by these transcription factors in vivo. (HEPATOLOGY 2010;)

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