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Departments of Molecular Cell Biology (K.T., A.D., A.A.) and Biological Regulation (Z.Y., R.S.), Weizmann Institute of Science, Rehovot 71600, Israel; and Department of Obstetrics and Gynecology (F.K.), Fukui Medical University, Fukui 910-1193, Japan
Address all correspondence and requests for reprints to: Abraham Amsterdam, Ph.D., Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: abraham.amsterdam{at}weizmann.ac.il.
Gonadotropins were recently demonstrated to be able to activate the MAPK cascade, but the physiological significance of this activation is still obscure. In the present work we demonstrate that highly luteinized human granulosa cells obtained from in vitro fertilization patients respond to human LH as well as to forskolin in phosphorylation of extracellular-signal regulated kinases 1 and 2 (ERK1 and -2). Moreover, the potent MAPK inhibitors, PD98059 and UO126, augment progesterone production in these cell cultures concomitantly with specific elevation of intracellular steroidogenic acute regulatory protein (StAR). Intracellular levels of the cytochrome P450 side-chain cleavage enzyme system do not seem to be affected. Similar observations were made with rat preovulatory or preantral granulosa cells stimulated with LH, FSH, or forskolin. Elevation of StAR expression by the MAPK inhibitors involved elevation of StAR mRNA, as demonstrated by RT-PCR in the human cells. Immunocytochemical studies using specific antibodies to StAR demonstrate a higher content of mitochondrial StAR in control as well as in gonadotropin-stimulated cells in the presence of PD98059 compared with cells not treated with PD98059. The cultured cells express the transcription factor steroidogenic factor-1 (SF-1), the phosphorylation of which is known to activate the expression of StAR, as well as dosage-sensitive sex reversal adrenal hypoplasia congenita, critical region on the X chromosome gene-1 (DAX-1), which is known to negate SF-1 activity. Intracellular levels of DAX-1 decreased significantly during 24 h of incubation of cells with or without LH in the presence of PD98059 or UO126 compared with those in cultures incubated in the absence of the MAPK inhibitors. The expression of SF-1 was suppressed by LH, whereas MAPK inhibitor could block this effect and further elevate SF-1 levels. Thus, activation of the MAPK cascade by gonadotropins may serve as a novel mechanism to down-regulate steroidogenesis via attenuation of StAR expression. Moreover, modulation of DAX-1 and SF-1 intracellular levels in these cells suggests that these transcription factors could be involved in MAPK suppression of StAR expression.
This work was supported by grants from the Levin Center and the Center of Excellence in Research at Weizmann Institute of Science (to A.A.), and from the Israel Academy of Sciences and Humanities (to R.S.).
A.A. is incumbent of the Joyce and Ben B. Eisenberg Professorial Chair in Molecular Endocrinology and Cancer Research.
Abbreviations: ADX, Adrenodoxin; 8-Br-cAMP, 8-bromo-cAMP; DAX-1, dosage-sensitive sex reversal adrenal hypoplasia congenita, critical region on the X chromosome gene-1; DNase, deoxyribonuclease; DP-, diphospho-; ERK, extracellular-signal regulated kinase; FCS, fetal calf serum; FK, forskolin; FSHR, FSH receptor; G-, general; h, human; hCG, human chorionic gonadotropin; Ig, immunoglobulin; IVF, in vitro fertilization; LHR, LH receptor; P450scc, cytochrome P450 side-chain cleavage enzyme; PKA, protein kinase A; SF-1, steroidogenic factor-1; StAR, steroidogenic acute regulatory protein.
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