p53 Mediates GnRH Secretion via Lin28/let-7 System in GT1-7 Cells

STUDY OBJECTIVE: The well-known tumor suppressor transcriptional factor p53 has been proposed to be one of the central hubs of a functionally related and hierarchically arranged gene network coordinating pubertal timing. Our previous studies revealed that p53 is involved in the metabolic control of puberty. The current study aimed to investigate the underlying signaling pathway, through which p53 mediated the metabolic control of puberty. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We engineered the expression of p53 and/or Lin28a in GT1-7 cells to investigate the interaction between p53 and Lin28/let-7 system, and their impact on GnRH secretion. RESULTS: Overexpression of p53 stimulated, while inhibition of p53 by pifithrin-α significantly suppressed the GnRH secretion and GPR54 expression levels in response to kisspeptin stimulation in GT1-7 cells. Furthermore, overexpressed p53 suppressed Lin28a and c-Myc expression levels and increased let-7 expression levels in GT1-7 cell lines. On the other hand, inhibition of p53 by pifithrin-α upregulated Lin28a and c-Myc levels and downregulated let-7 expression levels. Moreover, Lin28a overexpression counteracted the effect of p53 overexpression in p53 and Lin28a co-overexpression cells, whose GnRH secretion and GPR54 expression levels were not different from controls. Meanwhile, Lin28a suppression counteracted the effect of pifithrin-α, and the GnRH secretion and GPR54 expression levels are not different from controls in p53 and Lin28a co-suppression cells. CONCLUSION: These data suggest that p53 is a central mediator of GnRH secretion in hypothalamus, and this effect is at least partly through the Lin28/let-7 pathway.