Graduate Program in Genes and Development, University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
Hepatology. 2010 Sep;52(3):1023-32. doi: 10.1002/hep.23746.
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-p73alpha, and TA-p73beta isoforms.
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.
p53 蛋白家族调节细胞周期阻滞和细胞凋亡的靶基因的表达，这可能与细胞生长控制以及肿瘤抑制有关。在 p53 家族中，p53 和反式激活的 p73 同种型（TA-p73）在发育和肿瘤抑制中具有肝脏特异性功能。在这里，我们确定了 TA-p73 在成年小鼠肝脏中的染色质相互作用，并发现叉头框 O3（Foxo3）是 158 个基因靶标之一。在再生肝脏与静止肝脏的肝脏基因表达的全局分析中，发现了在再生过程中受调节的特定、功能类别基因。在转录因子中，Foxo3 是表达改变最明显的基因之一，在细胞增殖再生期间表达改变。p53 和 TA-p73 结合 Foxo3 p53 反应元件（p53RE），并在静止肝脏中保持活性表达。在肝脏再生期间，p53 和 TA-p73 的结合、乙酰转移酶 p300 的募集以及 Foxo3 的活性染色质结构与 Foxo3 表达的丧失一起被破坏。与 Foxo3 转录激活的丧失一致，在小鼠肝部分切除后，在 Foxo3 p53RE 检测到组蛋白激活标记（赖氨酸 4 二甲基化组蛋白 H3、赖氨酸 14 乙酰化组蛋白 H3 和乙酰化 H4）的减少。这些 Foxo3 调节参数在肝生长和再生完成时重新建立，并支持在组织再生过程中正常细胞中 p53 和 TA-p73 调节功能的暂时暂停。在小鼠胚胎成纤维细胞和过表达 p53、TA-p73alpha 和 TA-p73beta 同种型的小鼠肝癌细胞中，也观察到 p53 依赖性和 TA-p73 依赖性 Foxo3 激活。
p53 和 p73 直接结合并激活成年小鼠肝脏和小鼠细胞系中 Foxo3 基因的表达。p53、TA-p73 和 p300 结合以及 Foxo3 表达在肝再生期间减少，这表明这些转录因子在体内介导了关键的生长控制机制。
