Van Nostrand Jeanine L, Bowen Margot E, Vogel Hannes, Barna Maria, Attardi Laura D
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Death Differ. 2017 Apr;24(4):575-579. doi: 10.1038/cdd.2016.128. Epub 2017 Feb 17.
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.
p53肿瘤抑制因子是一个多蛋白家族的成员，包括p63和p73转录因子。这些蛋白能够结合DNA中的相同共有序列位点并激活相同的靶基因，这表明它们之间可能存在功能冗余。实际上，对于任何两个编码家族成员的基因而言，双突变杂合子小鼠相对于单杂合子突变体表现出增强的癌症表型。然而，这些家族成员在胚胎发育过程中是否发挥冗余作用在很大程度上仍未得到探索。尽管p53；p73双突变小鼠能够出生并表现出每个单突变体的特征性表型，但p63与p53或p73联合缺失所产生的后果尚未阐明。为了研究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的表型。我们发现双敲除胚胎和五等位基因敲除胚胎仅表现出由单个p53家族成员缺失所导致的明显缺陷。令人惊讶的是，在妊娠中期（E11），我们鉴定出了一个存活的三敲除胚胎，其外观大体正常。综上所述，这些结果表明p53家族并非早期胚胎发生绝对必需的，并且p53家族成员在早期发育过程中在很大程度上并非冗余的。
