Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene network
Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene network
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DOI：
10.1038/sj.cdd.4402075
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发表时间：
2007-04-01
影响因子：
12.4
通讯作者：
Rothman, J. H.
中科院分区：
文献类型：
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作者：
Derry, W. B.;Bierings, R.;Rothman, J. H.
秀丽隐杆线虫CEP-1激活生殖细胞凋亡响应基因毒性应激，类似于它的哺乳动物对应物，肿瘤抑制基因p53。在哺乳动物中，有三个p53家族成员（p53，p63和p73）激活和抑制许多不同和重叠的基因组，揭示了一个复杂的转录调控网络。由于CEP-1是C.在这种生物体中，对这个网络的分析大大简化了。我们发现，CEP-1在正常发育过程中，在没有压力的情况下，抑制许多（331）基因和激活只有少数（28）基因的功能。在应对遗传毒性应激时，1394个基因被激活，942个基因被抑制，其中许多基因含有p53结合位点。CEP-1转录网络与人p53家族的转录靶点的比较揭示了CEP-1调节的基因与人p63和p53调节的同源物之间的相当大的重叠，表明CEP-1的复合p53/p63作用。我们发现phg-1、C.线虫Gas 1（生长停滞特异性1）同源物，被CEP-1激活，并且是生殖系中响应于遗传毒性应激的细胞增殖的负调节因子。此外，我们发现CEP-1和PHG-1介导了调节寿命和检查点反应的EST-2/TEL 2基因突变的发育率和胚胎存活率降低。
Caenorhabditis elegans CEP-1 activates germline apoptosis in response to genotoxic stress, similar to its mammalian counterpart, tumor suppressor p53. In mammals, there are three p53 family members (p53, p63, and p73) that activate and repress many distinct and overlapping sets of genes, revealing a complex transcriptional regulatory network. Because CEP-1 is the sole p53 family member in C. elegans, analysis of this network is greatly simplified in this organism. We found that CEP-1 functions during normal development in the absence of stress to repress many (331) genes and activate only a few (28) genes. In response to genotoxic stress, 1394 genes are activated and 942 are repressed, many of which contain p53-binding sites. Comparison of the CEP-1 transcriptional network with transcriptional targets of the human p53 family reveals considerable overlap between CEP-1-regulated genes and homologues regulated by human p63 and p53, suggesting a composite p53/p63 action for CEP-1. We found that phg-1, the C. elegans Gas1 (growth arrest-specific 1) homologue, is activated by CEP-1 and is a negative regulator of cell proliferation in the germline in response to genotoxic stress. Further, we find that CEP-1 and PHG-1 mediate the decreased developmental rate and embryonic viability of mutations in the clk-2/TEL2 gene, which regulates lifespan and checkpoint responses.