The p53 family members have distinct roles during mammalian embryonic development
The p53 family members have distinct roles during mammalian embryonic development
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DOI：
10.1038/cdd.2016.128
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发表时间：
2017-04-01
影响因子：
12.4
通讯作者：
Attardi, Laura D.
中科院分区：
文献类型：
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作者：
Van Nostrand, Jeanine L.;Bowen, Margot E.;Attardi, Laura D.
P53抑癌基因是包括p63和p73转录因子在内的多蛋白家族的成员。这些蛋白质可以结合到DNA中相同的共识位置，并激活相同的目标基因，这表明它们之间可能存在功能冗余。事实上，与单一杂合突变相比，任何两个家族成员编码基因杂合的双突变小鼠表现出更强的癌症表型。然而，家庭成员在胚胎发育过程中是否扮演多余的角色在很大程度上仍未得到探索。虽然P53(-/-)；P73(-/-)小鼠出生后表现出每个单一突变体特有的表型，但p63和P53或P73联合缺失的后果尚未阐明。为了检测P53家族成员在发育过程中的功能重叠，我们培育并分析了复合突变胚胎表型。我们发现，双基因敲除胚胎和5个等位基因敲除胚胎仅表现出明显的缺陷，这是由于单个P53家族成员的缺失造成的。令人惊讶的是，在怀孕中期(E11)，我们发现了一个单一的可存活的三基因敲除胚胎，看起来非常正常。综上所述，这些结果表明，P53家族对于早期胚胎发育并不是绝对必要的，并且P53家族成员在早期发育过程中基本上是非多余的。
The p53 tumor suppressor is a member of a multi-protein family, including the p63 and p73 transcription factors. These proteins can bind to the same consensus sites in DNA and activate the same target genes, suggesting that there could be functional redundancy between them. Indeed, double mutant mice heterozygous for any two family member-encoding genes display enhanced cancer phenotypes relative to single heterozygous mutants. However, whether the family members play redundant roles during embryonic development has remained largely unexplored. Although p53(-/-); p73(-/-) mice are born and manifest phenotypes characteristic of each of the single mutants, the consequences of combined deficiency of p63 and either p53 or p73 have not been elucidated. To examine the functional overlap of p53 family members during development, we bred and analyzed compound mutant embryo phenotypes. We discovered that double knockout embryos and five allele knockout embryos only displayed obvious defects accounted for by loss of single p53 family members. Surprisingly, at mid-gestation (E11), we identified a single viable triple knockout embryo that appeared grossly normal. Together, these results suggest that the p53 family is not absolutely required for early embryogenesis and that p53 family members are largely non-redundant during early development.