Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Fully grown, but not growing, mammalian oocytes spontaneously resume meiosis in vitro. Resumption of meiosis, also known as oocyte maturation, is associated with a drop in intraoocyte concentrations of cAMP followed by activation of the maturation promoting factor (MPF). Microtubule-associated-protein (MAP) kinase has been suggested as a substrate for the active p34cdc2 kinase, the catalytic subunit of MPF. Our study was designed to explore the mechanism of regulation of meiotic arrest in growing rat oocytes. Confirming previous observations we showed that in our rat colony oocytes do not acquire the competence to spontaneously resume meiosis earlier than 22 days postpartum. We further demonstrated that follicle-enclosed oocytes from 20-day-old female rats fail to resume meiosis in response to luteinizing hormone, follicle-stimulating hormone, a gonadotropin-releasing hormone analog, or forskolin, all of which are known to induce maturation in competent oocytes. Immunoblot analysis using highly specific anti p34cdc2 antibodies revealed that incompetent oocytes express the catalytic subunit of MPF at amounts that are not different from that found in competent oocytes. In addition, highly specific anti MAP kinase antibodies detected the presence of similar quantities of two isoforms (42 and 44 kDa) of MAP kinase in competent and incompetent oocytes. Measurements of cAMP revealed that as compared to competent oocytes, incompetent oocytes contain somewhat lower levels of this nucleotide (1.42 +/- 0.3 and 1.17 +/- 0.07 fmole/oocyte, respectively). However, considering the difference in protein content, the calculated concentrations seem to be similar. Furthermore, similar to competent oocytes, intracellular concentrations of cAMP in incompetent oocytes dropped significantly (from 1.17 +/- 0.07 to 0.77 +/- 0.12 fmole/oocyte) 2 hr after isolation from the follicle. We hereby suggest that (a) in mammals, similar to amphibians, the term meiotic incompetence can be extended to include inability to resume meiosis in response to hormonal stimulation; (b) it is not the lack of p34cdc2 or downstream regulatory elements, such as MAP kinase, that prevents growing oocytes from resuming meiosis; and (c) unlike fully grown oocytes, resumption of meiosis in growing oocytes is not subjected to negative regulation by cAMP.
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PMID:Meiotic arrest in incompetent rat oocytes is not regulated by cAMP. 795 38

Gonadotropin-releasing hormone (GnRH), the first key hormone of reproduction, is synthesized in the hypothalamus and is released in a pulsatile manner to stimulate pituitary gonadotrope-luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and release. Gonadotropes represent only about 10% of pituitary cells and are divided into monohormonal cells (18% LH and 22% FSH cells) and 60% multihormonal (LH + FSH) cells. GnRH binds to a specific seven transmembrane domain receptor which is coupled to Gq and activates sequentially different phospholipases to provide Ca2+ and lipid-derived messenger molecules. Initially, phospholipase C is activated, followed by activation of both phospholipase A2 (PLA2) and phospholipase D (PLD). Generation of the second messengers inositol 1,4,5-trisphosphate and diacylglycerol (DAG) lead to mobilization of intracellular pools of Ca2+ and activation of protein kinase C (PKC). Early DAG and Ca2+, derived via enhanced phosphoinositide turnover, might be involved in rapid activation of selective Ca(2+)-dependent, conventional PKC isoforms (cPKC). On the other hand, late DAG, derived from phosphatidic acid (PA) via PLD, may activate Ca(2+)-independent novel PKC isoforms (nPKC). In addition, arachidonic acid (AA) which is liberated by activated PLA2, might also support selective activation of PKC isoforms (PKCs) with or without other cofactors. Differential cross-talk of Ca2+, AA, and selective PKCs might generate a compartmentalized signal transduction cascade to downstream elements which are activated during the neurohormone action. Among those elements is the mitogen-activated protein kinase (MAPK) cascade which is activated by GnRH in a PKC-, Ca(2+)-, and protein tyrosine kinase (PTK)-dependent fashion. Transcriptional regulation can be mediated by the activation of transcription factors such as c-fos by MAPK. Indeed, GnRH activates the expression of both c-jun and c-fos which might participate in gene regulation via the formation of AP-1. The signaling cascade leading to gonadotropin (LH and FSH) gene regulation by GnRH is still not known and might involve the above-mentioned cascades. AA and selective lipoxygenase products such as leukotriene C4 also participate in GnRH action, possibly by cross-talk with PKCs, or by an autocrine/paracrine amplification cycle. A complex combinatorial, spatial and temporal cross-talk of the above messenger molecules seems to mediate the diverse effects elicited by GnRH, the first key hormone of the reproductive cycle.
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PMID:Mechanism of GnRH receptor signaling: combinatorial cross-talk of Ca2+ and protein kinase C. 946 87

Type 1 angiotensin II (ANG II) receptors play crucial roles in the regulation of blood pressure and fluid osmolarity, whereas the physiological roles of type 2 ANG II receptors (AT2) remain unclear. Because AT2 is expressed in atretic follicles where granulosa cells undergo apoptosis, we examined the space and time relationship between AT2 expression and follicle atresia in vivo and the effect of AT2 on follicle-stimulating hormone (FSH) actions in vitro. Binding studies, autoradiography, and RT-PCR of AT2 revealed that the AT2 content in granulosa cells was time dependently increased at both protein and mRNA levels in equine chorionic gonadotropin-treated immature female rats. This increase paralleled the progression of atresia. ANG II suppressed FSH-caused prevention of DNA fragmentation, increases in luteinizing hormone receptor content, and estrogen production through AT2 in cultured granulosa cells. Moreover, FSH-induced stimulation of extracellular signal-regulated kinase activity, critical for cell survival, was inhibited by AT2 stimulation. These results suggest that AT2 mediates the progression of follicle atresia through granulosa cell apoptosis by inhibiting FSH actions.
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PMID:Biological roles of angiotensin II via its type 2 receptor during rat follicle atresia. 988 47

The appropriate, regulated expression of the glycoprotein hormone subunit genes is required to enable the biosynthesis of luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, and chorionic gonadotropin. We have focused our attention on mechanisms mediating regulated transcription of the common alpha-subunit gene. Our studies have examined both the signaling mechanisms and the DNA elements and transcription factors that are important for alpha-subunit expression. Our initial efforts involved characterization of DNA elements of the alpha-subunit gene important for basal and GnRH-stimulated expression. Clustered point mutation analysis identified two different, unrelated sequences that play a role in alpha-subunit transcription. When tested as multiple copies on a minimal promoter, one of these elements was sufficient to permit a response to GnRH, while the other enhanced basal expression. Therefore, we designated these DNA elements as the GnRH-response element (GnRH-RE) and the pituitary glycoprotein hormone basal element (PGBE), respectively. The GnRH-RE contains a consensus binding site for the Ets family of transcription factors. As several Ets factors have been shown to mediate transcriptional responses to the mitogen-activated protein kinase (MAPK) pathway, we investigated the possibility that GnRH effects on alpha-subunit transcription may involve the MAPK cascade. We found that GnRH can indeed activate MAPK and that MAPK activation is sufficient and necessary for transcriptional activation of the alpha-subunit gene. Efforts to further characterize proteins that interact with the PGBE led to the cloning of a LIM-homeodomain transcription factor designated LH-2. Recombinant LH-2 selectively binds to the PGBE in vitro. Transfection experiments have shown that an expression vector for LH-2 can activate the alpha-subunit promoter in heterologous cells. LH-2 appears to be a component of the endogenous factors that bind to the PGBE. Thus, LH-2 appears to be an excellent candidate as a factor responsible for basal expression of the alpha-subunit gene. Overall, these studies have contributed to identification of molecular components important for regulated expression of the glycoprotein hormone alpha-subunit gene.
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PMID:Regulation of glycoprotein hormone alpha-subunit gene expression. 1054 87

The response of granulosa cells to luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is mediated mainly by cAMP/protein kinase A (PKA) signaling. Notably, the activity of the extracellular signal-regulated kinase (ERK) signaling cascade is elevated in response to these stimuli as well. We studied the involvement of the ERK cascade in LH- and FSH-induced steroidogenesis in two granulosa-derived cell lines, rLHR-4 and rFSHR-17, respectively. We found that stimulation of these cells with the appropriate gonadotropin induced ERK activation as well as progesterone production downstream of PKA. Inhibition of ERK activity enhanced gonadotropin-stimulated progesterone production, which was correlated with increased expression of the steroidogenic acute regulatory protein (StAR), a key regulator of progesterone synthesis. Therefore, it is likely that gonadotropin-stimulated progesterone formation is regulated by a pathway that includes PKA and StAR, and this process is down-regulated by ERK, due to attenuation of StAR expression. Our results suggest that activation of PKA signaling by gonadotropins not only induces steroidogenesis but also activates down-regulation machinery involving the ERK cascade. The activation of ERK by gonadotropins as well as by other agents may be a key mechanism for the modulation of gonadotropin-induced steroidogenesis.
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PMID:The ERK signaling cascade inhibits gonadotropin-stimulated steroidogenesis. 2855 Jan 33

We examined the phosphorylation and acetylation of histone H3 in ovarian granulosa cells stimulated to differentiate by follicle-stimulating hormone (FSH). We found that protein kinase A (PKA) mediates H3 phosphorylation on serine 10, based on inhibition exclusively by PKA inhibitors. FSH-stimulated H3 phosphorylation in granulosa cells is not downstream of mitogen-activated protein kinase/extracellular signal-regulated kinase, ribosomal S6 kinase-2, mitogen- and stress-activated protein kinase-1, p38 MAPK, phosphatidylinositol-3 kinase, or protein kinase C. Transcriptional activation-associated H3 phosphorylation on serine 10 and acetylation of lysine 14 leads to activation of serum glucocorticoid kinase, inhibin alpha, and c-fos genes. We propose that phosphorylation of histone H3 on serine 10 by PKA in coordination with acetylation of H3 on lysine 14 results in reorganization of the promoters of select FSH responsive genes into a more accessible configuration for activation. The unique role of PKA as the physiological histone H3 kinase is consistent with the central role of PKA in initiating granulosa cell differentiation.
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PMID:Follicle-stimulating hormone stimulates protein kinase A-mediated histone H3 phosphorylation and acetylation leading to select gene activation in ovarian granulosa cells. 1149 42

Primary cultures of Sertoli cells provide an interesting model to study how signalling pathways induced by a single hormone in a single cell type evolve, depending on the developmental stage. In vivo, follicle-stimulating hormone (FSH) induces proliferation of Sertoli cells in neonate and controls the subsequent differentiation of the entire population. Molecular mechanisms underlying Sertoli cell pleiotropic responses to FSH have long been investigated. But to date, only cAMP-dependent kinase (PKA) activation has been reported to account for most FSH biological activities in male. Here, we demonstrate that FSH activates the ERK MAP kinase pathway following dual coupling of the FSH-R both to Gs and to Gi heterotrimeric proteins, in a PKA- and also Src-dependent manner. This activation is required for FSH-induced proliferation of Sertoli cells isolated 5 days after birth. Consistently, we show that the ERK-mediated FSH mitogenic effect triggers upregulation of cyclin D1. In sharp contrast, at 19 days after birth, as cells proceed through their differentiation program, the ERK pathway is dramatically inhibited by FSH treatment. Taken together, these results show that FSH can exert opposite effects on the ERK signalling cascade during the maturation process of Sertoli cells. Thus, signalling modules triggered by the FSH-R evolve dynamically throughout development of FSH natural target cells.
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PMID:The ERK-dependent signalling is stage-specifically modulated by FSH, during primary Sertoli cell maturation. 1149 92

A major concept in mammalian ovarian physiology is that follicle-stimulating hormone (FSH) activates the granulosa cells (GCs) in the Graafian follicle to selectively produce estradiol, but not progesterone, during the follicular phase of the menstrual or estrous cycle. However, given the fact that FSH can induce production of both estradiol and progesterone by GCs cultured in vitro, it has been postulated for a long time that there is a factor present in the ovary that selectively prevents FSH-induced progesterone production. Here, we provide evidence that two members of the mitogen-activated protein kinase family, extracellular signal-regulated kinase-1 and -2 (ERK1/2) can differentially regulate FSH-stimulated estradiol and progesterone production. Using primary rat GCs from early antral follicles cultured in serum-free medium for 48 h, we found that the addition of a specific inhibitor of ERK1/2 activation, U0126, caused the attenuation or enhancement of FSH-induced progesterone or estradiol production, respectively, in a dose-dependent manner. Throughout the 48-h culture period in this culture system ERK1/2 molecules in their activated state (phospho-ERK1/2) were clearly detectable in GCs exposed to FSH. The addition of U0126 caused a decrease in the levels of phosphorylated but not unphosphorylated ERK1/2 which was maintained throughout the 48-h culture, suggesting that U0126 was continuously active to inhibit the phosphorylation of ERK1/2. The divergent regulation of FSH-induced progesterone and estradiol synthesis by U0126 was further supported by demonstrating that U0126 inhibits and stimulates FSH-induced mRNA levels of steroidogenic acute regulatory protein and P450 aromatase, respectively. Collectively, this study clearly identified ERK1/2 as the first intracellular signaling molecules that differentially regulate FSH-induced progesterone and estradiol synthesis in GCs.
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PMID:Role of ERK1/2 in the differential synthesis of progesterone and estradiol by granulosa cells. 1173 15

The cellular adhesion status and the exposure to soluble growth factors both contribute to mitogen-activated protein (MAP) kinase activation. To date, however, whether mitogens acting through G-protein-coupled receptors (GPCRs) need cell adhesion to activate MAP kinases/extracellular signal-regulated kinases (ERK) 1, 2 has been poorly investigated. We addressed this point in primary cultures of Sertoli cells experimentally maintained in suspension, considering that follicle-stimulating hormone (FSH) activates ERK1, 2 in attached Sertoli cells by acting through a GPCR. We found that FSH actively repressed ERK1, 2, in a cAMP-dependent but cAMP-dependent protein kinase (PKA)-independent manner, and this inhibition required the activity of a tyrosine phosphatase. In comparison, in the absence of anchorage, ERK1, 2 were still activated by epidermal growth factor, in a PKA-dependent manner. Altogether, these data suggest that sensitivity of the MAP kinase response toward cell adhesion may depend, at least in part, on the class of receptor, GPCR or receptor with tyrosine kinase activity, by which it is triggered.
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PMID:Cellular adhesion of primary Sertoli cells affects responsiveness of the extracellular signal-regulated kinases 1 and 2 to follicle-stimulating hormone but not to epidermal growth factor. 1188 12

Bone morphogenetic protein-15 (BMP-15), an oocyte growth factor belonging to the transforming growth factor-beta superfamily, has recently been shown to be necessary for normal female fertility in mammals. We have previously demonstrated that BMP-15 regulates granulosa cell (GC) proliferation and differentiation; namely, BMP-15 promotes GC mitosis, suppresses follicle-stimulating hormone (FSH) receptor expression, and stimulates kit ligand expression. Although the role of BMP-15 in female reproduction has progressively deserved much attention, there is nothing known to date about the signaling pathway and receptors for BMP-15. Using rat primary GCs and a human GC cell line, COV434, we have now found that administration of BMP-15 causes a rapid and transient phosphorylation, thus activation, of the Smad1/5/8 pathway. BMP-15 also stimulated promoter activity of a selective BMP-responsive reporter construct, further demonstrating the stimulation of Smad1/5/8 signaling by BMP-15. In contrast, BMP-15 stimulation of Smad2 phosphorylation was very weak. To identify the receptors for BMP-15, we utilized recombinant extracellular domains of individual transforming growth factor-beta superfamily receptors and found that activin receptor-like kinase-6 extracellular domain most effectively co-immunoprecipitates with BMP-15, whereas BMP receptor type II extracellular domain was most effective in inhibiting BMP-15 bioactivity on FSH-induced progesterone production and GC thymidine incorporation. We also investigated whether activation of the MAPK pathway is necessary for BMP-15 biological activity and found that the addition of U0126, an inhibitor of ERK1/2 phosphorylation, suppresses BMP-15 activity on GC mitotsis but not on FSH-induced progesterone production, suggesting a selective signaling cascade in GC proliferation and differentiation.
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PMID:Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells. 1241 20


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