Direct activation of forkhead box O3 by tumor suppressors p53 and p73 is disrupted during liver regeneration in mice.
Direct activation of forkhead box O3 by tumor suppressors p53 and p73 is disrupted during liver regeneration in mice.
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DOI：
10.1002/hep.23746
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发表时间：
2010-09
期刊：
影响因子：
13.5
通讯作者：
Barton, Michelle Craig
中科院分区：
文献类型：
--
作者：
Kurinna, Svitlana;Stratton, Sabrina A.;Tsai, Wen-Wei;Akdemir, Kadir C.;Gu, Weisong;Singh, Pallavi;Goode, Triona;Darlington, Gretchen J.;Barton, Michelle Craig
p53蛋白家族调节促进细胞周期停滞和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与成年小鼠肝脏染色质的相互作用，并发现叉头因子Foxo 3作为158个基因靶点之一。再生与静止肝脏中肝脏基因表达的全球概况显示，随着再生时间的推移，基因的调控具有特定的功能类别。Foxo 3是在再生、细胞增殖期间具有改变的表达的转录因子中最响应的基因。p53和TA-p73结合Foxo 3 p53反应元件并在静止肝脏中维持活性表达。在肝脏再生过程中，p53和TA-p73的结合、乙酰转移酶p300的募集和Foxo 3的活性染色质结构被破坏，同时Foxo 3表达丧失。与Foxo 3转录激活的丧失一致，在小鼠部分肝切除术后检测到Foxo 3 p53 RE处的组蛋白激活标记（H3 K4 me 2、H3 K14 Ac和H4 Ac）减少。Foxo 3调节的这些参数在肝脏生长和再生完成时重新建立，支持组织再生期间正常细胞中p53和TA-p73调节功能的暂时中止。在小鼠胚胎成纤维细胞和过表达p53、TA-p73α和TA-p73β同种型的小鼠肝癌细胞中也观察到Foxo 3的p53和TA-p73依赖性活化。p53和p73直接结合并激活Foxo 3基因在成年小鼠肝脏和鼠细胞系中的表达。p53，TA-p73和p300结合和Foxo 3表达在肝再生过程中减少，表明这些转录因子在体内介导的关键生长控制机制。
The p53-family of proteins regulates 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 TA-p73 have hepatic-specific functions in development and tumor suppression. Here, we determined TA-p73-interactions with chromatin in adult mouse liver and found Forkhead factor Foxo3 as one of 158 gene targets. Global profiling of hepatic gene expression in regenerating versus quiescent liver revealed specific, functional categories of genes regulated over 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 and maintain active expression in quiescent liver. During regeneration of liver, binding of p53 and TA-p73, recruitment of acetyltransferase p300 and an active chromatin structure of Foxo3 are disrupted, alongside loss of Foxo3 expression. Consistent with the loss of Foxo3 transcriptional activation, a decrease of histone activation marks (H3K4me2, H3K14Ac and H4Ac) at Foxo3 p53RE was detected following partial hepatectomy in mice. These parameters of Foxo3 regulation are reestablished at completion of liver growth and regeneration, supporting a temporary suspension of p53 and TA-p73 regulatory functions in normal cells during tissue regeneration. p53 and TA-p73-dependent activation of Foxo3 is also observed in mouse embryonic fibroblasts and in mouse hepatoma cells overexpressing p53, TA-p73α and TA-p73β isoforms. p53 and p73 directly bind and activate expression of Foxo3 gene in adult mouse liver and murine cell lines. p53, TA-p73, and p300 binding and Foxo3 expression decrease during liver regeneration, suggesting a critical growth control mechanism mediated by these transcription factors in vivo.
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影响因子：
64.5
作者：
Avantaggiati, ML;Ogryzko, V;Kelly, K
通讯作者：
Kelly, K
影响因子：
5.3
作者：
Lecona, E.;Barrasa, J. I.;Lizarbe, M. A.
通讯作者：
Lizarbe, M. A.
影响因子：
20.3
作者：
Secchiero, Paola;Melloni, Elisabetta;Zauli, Giorgio
通讯作者：
Zauli, Giorgio
影响因子：
14.9
作者：
Smeenk L;van Heeringen SJ;Koeppel M;van Driel MA;Bartels SJ;Akkers RC;Denissov S;Stunnenberg HG;Lohrum M
通讯作者：
Lohrum M
影响因子：
50.3
作者：
Flores, ER;Sengupta, S;Jacks, T
通讯作者：
Jacks, T