Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice
Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice
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DOI：
10.1172/jci40051
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发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Dey, Sudhansu K.
中科院分区：
文献类型：
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作者：
Hirota, Yasushi;Daikoku, Takiko;Dey, Sudhansu K.
许多导致肿瘤发生的信号通路在妊娠期也有功能，尽管它们在妊娠期失调，而在妊娠期受到严格调控。转化相关蛋白53 （Trp53）编码p53，是一种肿瘤抑制基因，其突变与癌症密切相关。然而，它在包括女性生殖在内的正常生理过程中的作用却知之甚少。具有Trp53组成性缺失的小鼠在早期生殖年龄表现出广泛的致癌发展，精子发生受损和胎儿畸形，使得它们不太适合研究p53在生殖中的作用。为了克服这一障碍，我们培养了子宫Trp53条件缺失的小鼠，并检测了具有该基因型的雌性小鼠的妊娠结局。这些小鼠具有正常的排卵、受精和着床；然而，随着Akt和p21磷酸化水平的升高，植入后子宫蜕细胞表现出终末分化和衰老相关的生长限制，这两个因子在其他系统中都参与了这些过程。引人注目的是，子宫中Trp53的缺失增加了早产的发生率，这种情况可以通过口服选择性COX2抑制剂塞来昔布来纠正。我们进一步提出证据表明子宫Trp53的缺失会导致早产。通过COX2/PGF合成酶/PGF（2 α）途径出生。综上所述，我们的观察强调了我们认为子宫p53在分娩中的一个新的关键作用。
Many signaling pathways that contribute to tumorigenesis are also functional in pregnancy, although they are dysregulated in the former and tightly regulated in the latter. Transformation-related protein 53 (Trp53), which encodes p53, is a tumor suppressor gene whose mutation is strongly associated with cancer. However, its role in normal physiological processes, including female reproduction, is poorly understood. Mice that have a constitutive deletion of Trp53 exhibit widespread development of carcinogenesis at early reproductive ages, compromised spermatogenesis, and fetal exencephaly, rendering them less amenable to studying the role of p53 in reproduction. To overcome this obstacle, we generated mice that harbor a conditional deletion of uterine Trp53 and examined pregnancy outcome in females with this genotype. These mice had normal ovulation, fertilization, and implantation; however, postimplantation uterine decidual cells showed terminal differentiation and senescence-associated growth restriction with increased levels of phosphorylated Akt and p21, factors that are both known to participate in these processes in other systems. Strikingly, uterine deletion of Trp53 increased the incidence of preterm birth, a condition that was corrected by oral administration of the selective COX2 inhibitor celecoxib. We further generated evidence to suggest that deletion of uterine Trp53 induces preterm. birth through a COX2/PGF synthase/PGF(2 alpha) pathway. Taken together, our observations underscore what we believe to be a new critical role of uterine p53 in parturition.