Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice

Abstract

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 2α pathway. Taken together, our observations underscore what we believe to be a new critical role of uterine p53 in parturition.

Determinants of uterine aging: lessons from rodent models

“…Using a uterine endometrium specific senescence mouse model with uterine selective deletion of p53 [77], previous studies have showed senescence-associated growth restriction and preterm labor caused by increased levels of phosphorylated Akt and p21 in the knockout decidual tissue [78,79]. This senescence program of the p53 knockout decidual tissue would lead to increased levels of COX2-derived PGs, which affected the contractility of the uterus directly (Figure 1), not through the indirect luteolysis.…”

“…These risk factors are known to contribute to the cellular senescence process and the genetic evidence proved that p53's downstream, mammalian target of rapamycin complex 1 (mTORC1) signaling plays a key role in uterine senescence and the timing of birth [80]. As aging is a cause of cellular senescence [81,82], and decidual senescence is proved to be associated with premature delivery [79], it is conceivable that uterine senescence imposed by maternal aging carries an increased risk for problematic parturition. In humans, the epidemiologic study indicates that increased maternal age is correlated with preterm delivery [15,83,84], and women of higher maternal age, who use assisted reproductive technologies to achieve pregnancy, may experience a higher incidence of preterm birth even when receiving oocytes from young donors [85,86].…”

Uterine FK506-binding protein 52 (FKBP52)–peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress

“…Decidual cells were isolated as described previously (34). Protein lysates were immunoprecipitated with an anti-FKBP52 antibody, and complexes were run on SDS/PAGE and immunoblotted using antibodies specific to PRDX6 or FKBP52.…”

EPAC2-mediated calreticulin regulates LIF and COX2 expression in human endometrial glandular cells

“…It has been shown that uterine-specific p53-knockout mice exhibit senescence-associated growth restriction with an increase in endometrial SA-b-Gal activity and p21 expression and experience preterm labor (Hirota et al 2010). On the basis of these findings, it is conceivable that cellular senescence in EPAC2-or CALR-silenced EM1 cells could impair the production of implantation-related factors due in part to the reduction in CALR-mediated expression of p53 or p21.…”