Mechanisms involved in p53 downregulation by leptin in trophoblastic cells

TORO, AYELÉN R; PEREZ PEREZ, ANTONIO; CORRALES GUTIERREZ, ISABEL; SANCHEZ-MARGALET, VICTOR; VARONE, CECILIA

PLACENTA

W B SAUNDERS CO LTD

Lugar: Londres; Año: 2015 vol. 11 p. 1266 - 1275

0143-4004

Leptin, a 16-kDa polypeptide hormone, is produced by the adipocyte and can also be synthesized by placenta. We previously demonstrated that leptin promotes proliferation and survival in placenta, in part mediated by the p53 pathway. But the signaling pathways involved in leptin down-regulation of p53 level are unknown. Therefore, the objective of this study was to evaluate the participation of MAPK and PI3K/Akt pathways in leptin effect on p53 levels under serum deprivation. The human first trimester cytotrophoblastic Swan-71 cell line and human placental explants at term were used. In order to study the late phase of apoptosis, experiments of DNA fragmentation were carried out and revealed that MAPK pathway is needed for leptin anti-apoptotic action in placental explants. We also found that leptin decreases p53 levels and the inhibitory leptin effect is lost when placental cells were pretreated with PD98059 or LY29004; or were transfected with dominant negative mutants of intermediates of these pathways, suggesting that MAPK and PI3K signalling pathways are necessaries for leptin action. Additionally, we determined that leptin diminished Ser-46 p53 phosphorylation and this effect in placental explants was mediated by the activation of MAPK and PI3K pathways. Finally, in order to assess leptin effect on p53 half-life we analyzed MDM-2 expression and performed experiments with cycloheximide, finding that leptin up-regulated MDM-2 expression and diminished p53 half-life. In summary, we provided some evidence suggesting that previously reported leptin anti-apoptotic effect seems to be mediated by MAPK and PI3K/akt pathways.