The tumor suppressor p53 induces expression of the pregnancy-supporting human chorionic gonadotropin (hCG)CGB7gene

Abstract

Successful pregnancy requires a functionally normal blastocyst encountering a receptive maternal endometrium. Interestingly, the cell cycle regulator and tumor suppressor p53 has been reported to support reproduction in mice by regulating the expression of the leukemia inhibitory factor gene in the maternal endometrium. However, in humans the hormonal system orchestrating successful pregnancy is considerably different from rodents. Particularly, the primate-specific dimeric glycoprotein hormone human chorionic gonadotropin (hCG) is essential for blastocyst implantation and maintenance of early human pregnancy. Here we provide evidence that p53 selectively induces expression of the hCGbeta7 (CGB7) gene. None of the other CGB genes was found to be regulated by p53. We show that expression of the CGB7 gene is upregulated upon p53 induction in human HFF, HCT116 and DLD1 cells as well as in cell preparations enriched in human primary first-trimester trophoblasts. The increase in CGB7 levels upon doxorubicin treatment is lost after siRNA-directed knockdown of p53. Furthermore, we describe CGB7 as a direct transcriptional target gene of p53 by identifying a p53-responsive element in the CGB7 promoter using reporter assays, electrophoretic mobility shift assays and chromatin immunoprecipitations. With these results we provide a new link between p53 transcriptional activity and human reproduction.

p53 can repress transcription of cell cycle genes through a p21WAF1/CIP1-dependent switch from MMB to DREAM protein complex binding at CHR promoter elements

“…HCT116 parental, HCT116 p53−/− and HCT116 p21−/− , kindly provided by Bert Vogelstein, 54 and NIH3T3 cells (ACC59, DSMZ) were grown as described 55 . Stably transfected HCT116 cell lines were created by transfecting promoter-reporter constructs based on the pGL4.14-Hygro vector (Promega) and selected with hygromycin (PAA) at a concentration of 500 mg/ml.…”

p53 and Cell Cycle Dependent Transcription of kinesin family member 23 (KIF23) Is Controlled Via a CHR Promoter Element Bound by DREAM and MMB Complexes

“…Transfections of control siRNA (medium GC content, Invitrogen) and validated Stealth™ p53 siRNA (Invitrogen, VHS40367) at a final concentration of 100 nM were performed with DharmaFECT-1 transfection reagent (Dharmacon, Chicago, IL, USA) at a final dilution of 1∶1000 according to the manufacturer’s instructions [36]. Cells were harvested after 48 hours.…”

The impact of TP53 Arg72Pro and R249S genetic variations on IVF-ET outcome

“…LIF-deficient female mice have a defect in reproduction due to the complete lack of uterine decidualization at the implantation stage that leads to the failure of blastocyst implantation. The levels of LIF protein increase at the time of expected implantation in fertile women.It has been suggested that ER (estrogen receptor) and p53 cooperate in the regulation of blastocyst implantation through the induction of LIF and CGB7 (Sohr and Engeland, 2011). Leukemia inhibitory factor (LIF) is a cytokine that has been the focus of many studies (Aghajanova et al, 2009;Allegra et al, 2009;Rashid et al, 2011).…”