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.
Keywords: pubertal timing, p53 , Lin28/let-7  system, gonadotropin-releasing hormone