The tumor suppressor p53 induces expression of the pregnancy-supporting human chorionic gonadotropin (hCG) CGB7 gene.
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.
Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.
Sindy
S
Sohr
Kurt
K
Engeland
D001483:Base Sequence; D001665:Binding Sites; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D011247:Pregnancy; D034622:RNA Interference; D020218:Response Elements; D016415:Sequence Alignment; D014327:Trophoblasts / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015854:Up-Regulation
D018997:Chorionic Gonadotropin, beta Subunit, Human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin