p53 regulates a mitotic transcription program and determines ploidy in normal mouse liver.
p53 regulates a mitotic transcription program and determines ploidy in normal mouse liver.
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p53 调节有丝分裂转录程序并确定正常小鼠肝脏中的倍性。
DOI：
10.1002/hep.26233
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发表时间：
2013-05
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.;Coban, Zeynep;Schumacher, Jill M.;Grompe, Markus;Duncan, Andrew W.;Barton, Michelle Craig
据报道，p53在有丝分裂期间的功能包括防止多倍体和传递异常染色体。然而，p53是否在体内基因组监测过程中发挥这些作用，如果是这样，通过直接或间接的手段仍然未知。正常成熟肝细胞对刺激做出反应、重新进入细胞周期和再生肝脏质量的能力为评估体内有丝分裂提供了理想的环境。在静止的肝脏中，正常情况下成年小鼠的高倍性水平随着p53的丢失而增加。部分肝切除术后，p53−/−肝细胞表现出早期进入细胞周期和延长增殖，多倍体有丝分裂数增加。在WT和p53−/−肝细胞的再生过程中，倍性水平增加，但只有WT肝细胞能够动态解析倍性水平，并在再生结束时恢复正常。我们确定了多种细胞周期和有丝分裂调节因子，包括Foxm 1，Aurka，Lats 2，Plk 2和Plk 4，在体内直接受p53染色质相互作用的调节。随着再生的时间进程，p53表达的直接和间接调节以基因特异性方式介导。我们的研究结果表明，p53在正常和再生肝细胞的有丝分裂保真度和倍性分辨率中发挥作用。
Functions of p53 during mitosis reportedly include prevention of polyploidy and transmission of aberrant chromosomes. However, whether p53 plays these roles during genomic surveillance in vivo and, if so, by direct or indirect means remain unknown. The ability of normal, mature hepatocytes to respond to stimuli, reenter cell cycle and regenerate liver mass offers an ideal setting to assess mitosis in vivo. In quiescent liver, normally high ploidy levels in adult mice increased with loss of p53. Following partial hepatectomy, p53−/− hepatocytes exhibited early entry into cell cycle and prolonged proliferation with an increased number of polyploid mitoses. Ploidy levels increased during regeneration of both WT and p53−/− hepatocytes, but only WT hepatocytes were able to dynamically resolve ploidy levels and return to normal by the end of regeneration. We identified multiple cell cycle and mitotic regulators, including Foxm1, Aurka, Lats2, Plk2 and Plk4, as directly regulated by chromatin interactions of p53 in vivo. Over a time course of regeneration, direct and indirect regulation of expression by p53 is mediated in a gene-specific manner. Our results show that p53 plays a role in mitotic fidelity and ploidy resolution in hepatocytes of normal and regenerative liver.
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