Rapamycin for life: A step to immortality

Tumor suppression is admittedly the moststudied feature of p53. Nevertheless, numerous studies have portrayed p53 as key regulator of several normal biological processes, such as tissue homeostasis, development, differentiation and fertility.1 A seminal work by Hu and colleagues revealed that p53 regulates maternal reproduction through leukemia inhibitory factor (LIF) induction in mice.2 A recent report by Sohr and Engeland extends this observation and suggests a role for p53 in the blastocyst implantation process in humans as well.3 The authors show that CGB7, one of the genes encoding the b subunit of human chorionic gonadotropin (hCG), is transcriptionally induced by p53. hCG is a primate-specific hormone that is crucial for blastocyst implantation and early propagation of pregnancy. Interestingly, the other hCG-b-encoding genes were not induced by p53, thus implying a specific regulation leading to different  functions of these closely related genes. Several studies have connected the p53 pathway to human reproduction at large. In regards to implantation, we know now that both the gene encoding LIF, which is an endometrial cytokine (maternal source) important for blastocyst implantation,4 and CGB7, which is secreted by trophoblasts (blastocyst source), are regulated by p53.3 This implies that p53 has a major role in balancing hormone production at the implantation site, and thus secures proper implantation (Fig. 1). Furthermore, in addition to p53, estrogen receptor (ER) also regulates LIF in the implantation stage.5 Concordantly, we found that the promoter of the human CGB7 gene contains two putative ER responsive elements (-833/-811 bp and -525/-503 bp upstream of the transcription start site of CGB7— NM_033142). Therefore, it is tempting to speculate that ER and p53 cooperate in the regulation of blastocyst implantation through the induction of LIF and CGB7 (Fig. 1). Although some p53 target genes are initially described in other biological processes, they might also be related to the transformation process. For example, LIF was reported to play a vital role in cancer, although its endpoint effect seems to be tumor-specific. For example, secretion of LIF seems to promote tumor growth,6 while, on the other hand, it is transcriptionally repressed in cancer-associated stroma7 and might be located near a tumor suppressor locus in meningiomas.8 As p53 counteracts transformation, one might speculate that CGB7, being a genuine p53 target, has antitumor activity as well. Hitherto, merely one study examined CGB7 in the context of cancer. The mRNA expression of all CGB family members in invasive breast tumors samples were examined, and no significant change in CGB7 expression was found.9 Future research should be aimed at uncovering the full details of p53’s mode of action in the implantation process in both blastocyst and maternal tissue and perhaps tie CGB7 to the transformation process as well.