Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GnRH acts on pituitary gonadotropes to stimulate the synthesis and release of LH and FSH. However, the signaling pathways downstream of the GnRH receptor that mediate these effects are not fully understood. In this paper, we demonstrate that GnRH activates ERK, c-Jun N-terminal kinase, and p38MAPK in the LbetaT2 gonadotrope cell line. Phosphorylation of both ERK and p38MAPK are stimulated rapidly, 30- to 50-fold in 5 min, but activation of c-Jun N-terminal kinase has slower kinetics, reaching only 10-fold after 30 min. Activation of ERK by GnRH is blocked by inhibition of MAPK kinase (MEK) and partially blocked by inhibition of PKC and calcium, but not PI3K or p38MAPK signaling. We demonstrate that phosphorylated ERK accumulates in the nucleus in a PKC-dependent manner. We also show that GnRH induces c-fos and LHbeta subunit protein expression in LbetaT2 cells via MEK. Experiments with EGTA or calcium channel antagonists indicated that calcium influx is important for the induction of both genes by GnRH. In conclusion, these results show that GnRH activates all three MAPK subfamilies in LbetaT2 cells and induces c-fos and LHbeta protein expression through calcium and MEK-dependent mechanisms. These results also demonstrate that the nuclear translocation of ERK by GnRH requires PKC signaling.
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PMID:GnRH activates ERK1/2 leading to the induction of c-fos and LHbeta protein expression in LbetaT2 cells. 1187 99

The gonadotropic hormones, FSH and LH exert a major effect on ovarian and testicular function through interaction with specific seven-transmembrane domain glycoprotein receptors. Desensitization to the hormones, which can occur both in vivo and in vitro, is essential for prevention of overstimulation of the gonadal cells. The long-term process of desensitization to the gonadotropic hormones is probably mediated, in part, by extensive clustering and internalization of the hormone-receptor complex. Short-term desensitization may occur as a result of phosphorylation of serine or threonine residues on the receptor molecules, although a specific receptor kinase has not yet been identified. Recently, we have discovered a novel mechanism of gonadotropin desensitization, which is exerted by down-regulation of StAR expression and steroidogenesis mediated by MAPK activation as a result of hormone-receptor interaction, cAMP accumulation and PKA activation. Thus, PKA not only mediates gonadotropin-induced steroidogenesis, it also activates the down-regulation mechanism that can silence steroidogenesis under certain conditions. Moreover, our findings raise the possibility that activation or inhibition of ERK by other pathways could be an important mechanism for diminution or amplification of gonadotropin-stimulated steroidogenesis. This could contribute to functional luteolysis, a process in which luteinized granulosa cells show reduced sensitivity to LH despite maintenance of LH receptors, or to up-regulation of the steroidogenic machinery during luteinization of granulosa cells.
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PMID:Mechanisms of gonadotropin desensitization. 1198 13

To investigate the role of FSH in ovarian cancer development, the present study examined the expression of FSH receptor (FSH-R) and the effect of FSH on proliferation of normal, preneoplastic, and neoplastic ovarian surface epithelium (OSE) cells. Recently, immortalized OSE (IOSE) cell lines, including IOSE-29 (preneoplastic) and IOSE-29EC (neoplastic), were used. Our results indicated that FSH-R mRNA was expressed and that FSH exerted a growth stimulatory effect in normal, preneoplastic, and neoplastic OSE cells. To investigate the mechanism of the growth stimulatory effect, the activation of MAPKs by FSH was examined in preneoplastic and neoplastic OSE cells. Treatment with FSH resulted in MAPK activation of IOSE-29 and IOSE-29EC cells, whereas the stimulatory effect of FSH on cellular proliferation and MAPK activation was completely abolished in the presence of PD98059, a MAPK kinase inhibitor, suggesting that the growth stimulatory effect of FSH is mediated through MAPK activation in these OSE cells. In a time-dependent study, FSH significantly increased MAPK activity at 5-10 min in IOSE-29 cells. The activated MAPK declined to the control level after 20 min in these cells. Similarly, treatment with FSH significantly induced MAPK activation after 5 min and sustained it for 60 min in IOSE-29EC cells. In addition, treatment with FSH resulted in substantial phosphorylation of Elk-1, confirming that FSH action is mediated via activation of MAPK. In conclusion, we have demonstrated that FSH-R was expressed, and FSH induced growth stimulation in normal, preneoplastic, and neoplastic OSE cells. Furthermore, treatment with FSH stimulated activation of the MAPK cascade and phosphorylated Elk-1 in neoplastic OSE cells. These results suggest that the MAPK cascade may be involved in cellular functions such as growth stimulation in response to FSH in preneoplastic and neoplastic OSE cells.
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PMID:Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovarian surface epithelial cells. 1199 71

Ovarian cancer is the most lethal gynecological cancer, and approximately 90% of ovarian cancers derive from the ovarian surface epithelium (OSE), yet the biology of the OSE is poorly understood. Factors associated with increased risk of non-hereditary ovarian cancer include the formation of inclusion cysts, effects of reproductive hormones and the number of ovulations experienced in a woman's lifetime. Distinguishing between these factors is difficult in vivo, but cultured OSE cells are viable tools for some avenues of research. Here we establish rhesus macaque OSE cultures and demonstrate that these cells express cytokeratin, vimentin, N-cadherin, ER-alpha, and PR but are negative for E-cadherin. We show that these cells activate MAPK and proliferate in response to extracellular calcium, as do human and rat OSE. In contrast, the gonadotropic hormones FSH (4-400 IU/liter), LH (8.5-850 IU/liter), and human CG (10-1000 IU/liter) fail to stimulate proliferation. We find that concentrations of progesterone and estrogen normally present in follicles just before ovulation ( approximately 1000 ng/ml) significantly decrease the number of mitotically active rhesus macaque OSE cells as determined by PCNA labeling, total cell count, and (3)H-thymidine uptake, whereas lower steroid concentrations have no effect.
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PMID:Proliferation of rhesus ovarian surface epithelial cells in culture: lack of mitogenic response to steroid or gonadotropic hormones. 1202 Nov 83

This study investigated the participation of MAPK in the resumption of meiosis [germinal vesicle breakdown (GVB)] in oocytes and cumulus expansion using oocyte-cumulus cell complexes (OCC) from Mos-null mice (Mos(tm1Ev)/Mos(tm1Ev), hereafter Mos(-/-)). MAPK activity was not detected in Mos(-/-) oocytes whether they matured in vivo or in vitro, with or without gonadotropin stimulation. Therefore, there are no pathways independent of MOS that activate MAPK during gonadotropin-induced maturation. In contrast, MAPK activity was always detected coincident with GVB in Mos(+/+) oocytes. Moreover, MAPK activity was detected in cumulus cells before gonadotropin-induced GVB in OCC regardless of genotype. A specific inhibitor (U0126) of MEK, a MAPKK required for MAPK activity, inhibited gonadotropin-induced GVB in OCC of both Mos(+/+) and Mos(-/-) mice. Activation of MAPK was downstream of elevation of cAMP. U0126 also inhibited cumulus expansion stimulated by FSH, epidermal growth factor, 8-bromo-cAMP, and recombinant growth differentiation factor-9. It is concluded that under the in vitro conditions used here, gonadotropin-induced GVB requires the participation of MAPK activity in the cumulus cells, but not in the oocyte. Moreover, the induction of cumulus expansion also requires the participation of MAPK, and this action is downstream of both elevation of cAMP and growth differentiation factor-9.
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PMID:Mitogen-activated protein kinase activity in cumulus cells is essential for gonadotropin-induced oocyte meiotic resumption and cumulus expansion in the mouse. 1202 Nov 86

Butyrolactone I specifically inhibits M-phase promoting factor activation and prevents the resumption of meiosis. These experiments were conducted to examine effects of butyrolactone I on pig oocytes in a serum-free maturation system. The first experiment was conducted to determine the effect of butyrolactone I (0-100 microM) on nuclear maturation. At concentrations of > or =12.5 microM, germinal vesicle breakdown was prevented in >90% of the oocytes after 24 h of culture. In the second experiment, the kinetics of in vitro maturation of butyrolactone I-treated oocytes was investigated. Oocytes were treated with 0 or 12.5 microM butyrolactone I and FSH for 20 h and then cultured with LH in the absence of butyrolactone I for another 24 h. Fewer butyrolactone I-treated oocytes reached MII stage at 36 h compared with controls (5.8% vs. 62.4%, P < 0.01). However, by 44 h, 83.4% of butyrolactone I-treated oocytes reached MII compared with 88.6% of controls. In the third experiment, butyrolactone I-treated oocytes were fertilized and cultured in vitro. No differences (P > 0.05) were found between controls and treated groups in cleavage rate, blastocyst rate, or mean number of cells per blastocyst. Effects of butyrolactone I on mitogen-activated protein kinase activation and localization of microfilaments and active mitochondria were examined by Western blot analysis and laser scanning confocal microscopy, respectively. The results suggested that although butyrolactone I reversibly inhibited germinal vesicle breakdown and mitogen-activated protein kinase activation, it did not affect mitochondrial and microfilament dynamics. Butyrolactone I is a potent inhibitor of nuclear maturation of porcine oocytes, and the inhibition is fully reversible.
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PMID:High developmental competence of pig oocytes after meiotic inhibition with a specific M-phase promoting factor kinase inhibitor, butyrolactone I. 1208 14

The present studies were conducted to address cellular mechanisms responsible for regulating steroidogenic acute regulatory protein (StAR) expression and progesterone synthesis at maturational stages corresponding to both the time of hen follicle selection, as well as before and after the LH surge in preovulatory follicle granulosa cells. A recently published report has established that mitogen-activated protein (MAP) kinase signaling induced by transforming growth factor alpha (TGFalpha) treatment blocks FSH-induced differentiation and StAR expression in cultured hen granulosa cells, whereas inhibitors of MAP kinase signaling enhance FSH-induced differentiation. The present in vitro studies demonstrate that in addition to MAP kinase signaling, activation of protein kinase C (PKC) blocks both FSH-induced StAR expression and the initiation of progesterone production in prehierarchal follicle granulosa cells, whereas the pharmacologic inhibitor of PKC, GF109203X, potentiates FSH-induced StAR expression and, as a consequence, the initiation of progesterone synthesis. Moreover, we demonstrate in granulosa cells collected from preovulatory follicles that although an acute increase in progesterone production in response to LH treatment requires rapid transcription and translation of StAR, the magnitude of progesterone production is rate-limited by one or more factors other than StAR (e.g., the P450 cholesterol side-chain enzyme). Finally, the rapid turnover of StAR protein, such as occurs following the withdrawal of LH, provides an additional mechanism for the tight regulation of progesterone production that occurs during the hen ovulatory cycle, and explains the rapid loss of steroidogenesis in the postovulatory follicle. In summary, data reported herein support the proposal that paracrine/autocrine factors (including but not necessarily limited to TGFalpha) prevent premature expression of StAR in prehierarchal follicle granulosa cells by more than one receptor-mediated signaling pathway. Furthermore, subsequent to follicle selection into the preovulatory hierarchy, StAR transcription and translation is necessary but not sufficient for the full potentiation of the preovulatory surge of serum progesterone.
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PMID:Relationship between steroidogenic acute regulatory protein expression and progesterone production in hen granulosa cells during follicle development. 1229 50

In the pituitary, activin stimulates the synthesis and release of FSH. However, the activin receptor signaling pathways that mediate these effects are poorly known. We investigated these mechanisms in primary ovine pituitary cells (POP) and in the murine LbetaT2 gonadotrope cell line. POP cells and LbetaT2 cells express the different activin receptors (types IA, IB, IIA, and IIB) and the Smad proteins (Smad-2, -3, -4, and -7). In both POP and LbetaT2 cells, activin activated several signaling pathways: Smad-2, extracellular regulated kinase-1/2 (ERK1/2), p38, and phosphatidylinositol 3'-kinase (PI3K)/Akt. Phosphorylation of ERK1/2 and p38 were stimulated (3- to 6-fold) rapidly in 5 min, whereas activation of both Smad-2 and Akt (3- to 5-fold) occurred later, in 60 min. Activin also increased the association of activin receptor IIB with PI3K. Using specific inhibitors, we demonstrated that the activation of Smad-2 was partially blocked by the inhibition of PI3K but not by the inhibition of ERK1/2 or p38, suggesting a cross-talk between the Smad and PI3K/Akt pathways. In both POP and LbetaT2 cells, FSH expression and secretion in response to activin were not altered by the inhibition of PI3K/Akt, ERK1/2, or p38 pathways, whereas they were reduced by about 2-fold by expression of a dominant negative of Smad-2 or the natural inhibitory Smad-7 in LbetaT2 cells. These results indicate that activin activates several signaling pathways with different time courses in both POP and LbetaT2 cells, but only the Smad-2 pathway appears to be directly implicated in FSH expression and release in LbetaT2 cells.
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PMID:Activin signaling pathways in ovine pituitary and LbetaT2 gonadotrope cells. 1260 25

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.
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PMID:Down-regulation of steroidogenic response to gonadotropins in human and rat preovulatory granulosa cells involves mitogen-activated protein kinase activation and modulation of DAX-1 and steroidogenic factor-1. 1272 88

Although FSH receptors are linked to the cAMP second messenger system, additional intracellular signaling pathways appear to be required for the induction of aromatase and the LH receptor during granulosa cell differentiation. We employed adenovirus vectors to modulate specific intracellular signaling systems in undifferentiated granulosa cells to identify the signaling pathway(s) that may be involved in the FSH-mediated induction of aromatase and the LH receptor. Expression of either the constitutively activated human LH receptor D578H or the constitutively active human G(s)alpha Q227L resulted in increased cAMP production without increasing aromatase activity or mRNA levels for the LH receptor. To explore the contributions of other pathways, we expressed the constitutively activated forms MAPK kinase (MEK) and protein kinase B (PKB). Neither MEK nor PKB alone increased estrogen or progesterone production by undifferentiated granulosa cells. Stimulation of granulosa cells by FSH in the presence of the constitutively active PKB, but not MEK, led to an amplification of FSH-induced aromatase and LH receptor mRNA levels, whereas a dominant negative PKB vector completely abolished the actions of FSH. The expression of the constitutively active PKB in combination with the constitutively active LH receptor D578H, the constitutively active G(s)alpha Q227L, or 8-bromo-cAMP led to an induction of aromatase as well as LH receptor mRNA comparable to that seen in cells stimulated with FSH alone. These results demonstrate that PKB is an essential component of the FSH-mediated granulosa cell differentiation and that both PKB and G(s)alpha signaling pathways are required.
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PMID:Protein kinase B is obligatory for follicle-stimulating hormone-induced granulosa cell differentiation. 1293 73


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