Pérez-Pérez Antonio, Maymó Julieta, Gambino Yésica, Dueñas José L, Goberna Raimundo, Varone Cecilia, Sánchez-Margalet Víctor
Departamento de Bioquímica Médica y Biología Molecular, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Seville, Spain.
Biol Reprod. 2009 Nov;81(5):826-32. doi: 10.1095/biolreprod.109.076513. Epub 2009 Jun 24.
Leptin was originally considered as an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in placenta, where it may work as an autocrine hormone, mediating angiogenesis, growth, and immunomodulation. Leptin receptor (LEPR, also known as Ob-R) shows sequence homology to members of the class I cytokine receptor (gp130) superfamily. In fact, leptin may function as a proinflammatory cytokine. We have previously found that leptin is a trophic and mitogenic factor for trophoblastic cells. In order to further investigate the mechanism by which leptin stimulates cell growth in JEG-3 cells and trophoblastic cells, we studied the phosphorylation state of different proteins of the initiation stage of translation and the total protein synthesis by [(3)H]leucine incorporation in JEG-3 cells. We have found that leptin dose-dependently stimulates the phosphorylation and activation of the translation initiation factor EIF4E as well as the phosphorylation of the EIF4E binding protein EIF4EBP1 (PHAS-I), which releases EIF4E to form active complexes. Moreover, leptin dose-dependently stimulates protein synthesis, and this effect can be partially prevented by blocking mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PIK3) pathways. In conclusion, leptin stimulates protein synthesis, at least in part activating the translation machinery, via the activation of MAPK and PIK3 pathways.
瘦素最初被认为是一种由脂肪细胞产生的信号分子，用于对新陈代谢进行中枢控制。然而，瘦素在生殖和妊娠过程中已被发现具有多效性作用，尤其是在胎盘组织中，它可能作为一种自分泌激素发挥作用，介导血管生成、生长和免疫调节。瘦素受体（LEPR，也称为Ob-R）与I类细胞因子受体（gp130）超家族成员具有序列同源性。事实上，瘦素可能起到促炎细胞因子的作用。我们之前发现瘦素是滋养层细胞的一种营养和促有丝分裂因子。为了进一步研究瘦素刺激JEG-3细胞和滋养层细胞生长的机制，我们通过在JEG-3细胞中掺入[³H]亮氨酸来研究翻译起始阶段不同蛋白质的磷酸化状态以及总蛋白质合成情况。我们发现，瘦素以剂量依赖的方式刺激翻译起始因子EIF4E的磷酸化和激活，以及EIF4E结合蛋白EIF4EBP1（PHAS-I）的磷酸化，后者释放EIF4E以形成活性复合物。此外，瘦素以剂量依赖的方式刺激蛋白质合成，并且这种效应可以通过阻断丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3激酶（PIK3）途径而部分受到抑制。总之，瘦素通过激活MAPK和PIK3途径刺激蛋白质合成，至少部分是通过激活翻译机制来实现的。
