Schild R L, Sonnenberg-Hirche C M, Schaiff W T, Bildirici I, Nelson D M, Sadovsky Y
Department of Obstetrics and Gynecology, and Cell Biology and Physiology, Washington University School of Medicine, Campus Box 8064, 4566 Scott Avenue, St. Louis, MO 63110-1094, USA.
Placenta. 2006 Feb-Mar;27(2-3):191-9. doi: 10.1016/j.placenta.2005.01.012.
Deficiency of either the mitogen-activated protein kinase p38 or the nuclear receptor PPARgamma results in disrupted vasculogenesis and abnormal development of the murine placenta. In addition, PPARgamma regulates differentiation of human trophoblasts. Here we tested the hypothesis that p38 plays an important role in the regulation of PPARgamma in primary human trophoblasts. We initially confirmed that cultured trophoblasts derived from normal term human placentas express p38 as well as its functional phosphorylated form. Whereas PPARgamma did not alter p38 expression, p38 inhibitors diminished the transcriptional activity of PPARgamma in primary trophoblasts. In addition, inhibition of p38 resulted in marked attenuation of PPARgamma-stimulated hCG production by cultured trophoblast. Our data support an effect of p38 on PPARgamma protein stability because p38 inhibition led to reduced expression of PPARgamma protein without a significant effect on PPARgamma mRNA, and this reduction was blocked by the protease inhibitor MG-132. Together, these data indicate that p38 regulates PPARgamma expression and activity in term human trophoblasts. Cross talk between p38 and PPARgamma signaling may play a role in modulating differentiation and function of the human placenta.
丝裂原活化蛋白激酶p38或核受体PPARγ的缺乏会导致小鼠血管生成紊乱和胎盘发育异常。此外，PPARγ调节人滋养层细胞的分化。在此，我们检验了p38在原代人滋养层细胞中对PPARγ的调节起重要作用这一假说。我们首先证实，源自正常足月人胎盘的培养滋养层细胞表达p38及其功能性磷酸化形式。虽然PPARγ不会改变p38的表达，但p38抑制剂会降低原代滋养层细胞中PPARγ的转录活性。此外，抑制p38会导致培养的滋养层细胞中PPARγ刺激的hCG产生显著减少。我们的数据支持p38对PPARγ蛋白稳定性的影响，因为抑制p38会导致PPARγ蛋白表达降低，而对PPARγ mRNA没有显著影响，并且这种降低被蛋白酶抑制剂MG-132阻断。总之，这些数据表明p38调节足月人滋养层细胞中PPARγ的表达和活性。p38与PPARγ信号之间的相互作用可能在调节人胎盘的分化和功能中起作用。
