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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. In breast cancer cells the predominant effect of synthetic progestins is long-term growth inhibition and arrest in G1 phase. Progestin-mediated growth arrest of T-47D breast cancer cells was preceded by inhibition of cyclin D1-Cdk4, cyclin D3-Cdk4, and cyclin E-Cdk2 kinase activities in vitro and reduced phosphorylation of pRB and p107. This was accompanied by decreases in the expression of cyclins D1, D3, and E, decreased abundance of cyclin D1- and cyclin D3-Cdk4 complexes, increased association of the cyclin-dependent kinase (CDK) inhibitor p27 with the remaining Cdk4 complexes, and changes in the molecular masses and compositions of cyclin E complexes. In control cells cyclin E eluted from Superdex 200 as two peaks of approximately 120 and approximately 200 kDa, with the 120-kDa peak displaying greater cyclin E-associated kinase activity. Following progestin treatment, almost all of the cyclin E was in the 200-kDa, low-activity form, which was associated with the CDK inhibitors p21 and p27; this change preceded the inhibition of cell cycle progression. These data suggest preferential formation of this higher-molecular-weight, CDK inhibitor-bound form and a reduced number of cyclin E-Cdk2 complexes as mechanisms for the decreased cyclin E-associated kinase activity following progestin treatment. Ectopic expression of cyclin D1 in progestin-inhibited cells led to the reappearance of the 120-kDa active form of cyclin E-Cdk2 preceding the resumption of cell cycle progression. Thus, decreased cyclin expression and consequent increased CDK inhibitor association are likely to mediate the decreases in CDK activity accompanying progestin-mediated growth inhibition.
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PMID:Mechanisms of cyclin-dependent kinase inactivation by progestins. 952 53

We investigated the regulation of steroidogenesis in a cell line of porcine granulosa origin, JC-410. Cells responded to the protein kinase-A activators, cholera toxin and forskolin, with increased accumulation of intracellular cAMP. Histochemically, cells were shown to contain 3beta-HSD, the enzyme which converts pregnenolone to progesterone. The JC-410 cells produced progesterone and responded to the protein kinase-A activators with an increase in progesterone synthesis. Progesterone levels were also increased by 25-hydroxycholesterol, pregnenolone, estradiol and androstenedione. Follicle-stimulating hormone and luteinizing hormone had no effect on cAMP or progesterone accumulation. Androstenedione was required for the synthesis of estradiol by JC-410 cells. Steady-state levels of mRNA for the steroidogenic enzymes 3beta-HSD and P450scc were increased by treatment with cholera toxin, whereas P450arom was not changed. These cells express the steroidogenic enzymes genes in a similar fashion to primary cultures of porcine granulosa cells. The JC-410 cells may represent a valuable model to study second messenger regulation and the molecular mechanisms involved in steroidogenesis in granulosa cells.
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PMID:Regulation of steroidogenesis in jc-410, a stable cell line of porcine granulosa origin. 1022 74

The insecticide dichlorodiphenyltrichloroethane (DDT) and its major metabolite p,p'-dichlorodiphenyldichloroethylene (DDE) have been implicated as endocrine-modulating chemicals. The DDT metabolite p, p'-DDE has been found contaminating human tissues and follicular fluid because of dietary exposure. We investigated the effects of DDE on progesterone synthesis in a stable porcine granulosa cell line, JC-410, and in primary cultures of porcine granulosa cells. Progesterone synthesis was not affected by 0.1-100 ng/ml DDE in the JC-410 cells. However, 10 ng/ml DDE increased 8-bromo-cAMP (8-Br-cAMP)-stimulated progesterone synthesis 0.4-fold (P < 0.05) over the levels observed with 1 mM 8-Br-cAMP alone. The effect of cholera toxin (CT) on progesterone synthesis was increased 0.7-fold (P < 0.05) by 10 ng/ml DDE over the value observed with 30 ng/ml CT alone. In primary cultures of porcine granulosa cells, 10 ng/ml DDE potentiated CT-stimulated progesterone synthesis 1.2-fold over the value observed with CT alone. In the JC-410 cells, 1 and 10 ng/ml DDE increased CT-stimulated cytochrome P450-cholesterol side-chain cleavage (P450(scc)) mRNA levels 0.3- and 0.4-fold, respectively, over the values obtained with CT alone. Neither basal nor CT-stimulated cAMP levels were changed by DDE. We conclude that DDE affects granulosa cell response to protein kinase A activators by altering the expression of the P450(scc) gene.
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PMID:Dichlorodiphenyldichloroethylene potentiates the effect of protein kinase A pathway activators on progesterone synthesis in cultured porcine granulosa cells. 1049 49

Progesterone-induced meiotic maturation of Xenopus oocytes requires the synthesis of new proteins, such as Mos and cyclin B. Synthesis of Mos is thought to be necessary and sufficient for meiotic maturation; however, it has recently been proposed that newly synthesized proteins binding to p34(cdc2) could be involved in a signaling pathway that triggers the activation of maturation-promoting factor. We focused our attention on cyclin B proteins because they are synthesized in response to progesterone, they bind to p34(cdc2), and their microinjection into resting oocytes induces meiotic maturation. We investigated cyclin B accumulation in response to progesterone in the absence of maturation-promoting factor-induced feedback. We report here that the cdk inhibitor p21(cip1), when microinjected into immature Xenopus oocytes, blocks germinal vesicle breakdown induced by progesterone, by maturation-promoting factor transfer, or by injection of okadaic acid. After microinjection of p21(cip1), progesterone fails to induce the activation of MAPK or p34(cdc2), and Mos does not accumulate. In contrast, the level of cyclin B1 increases normally in a manner dependent on down-regulation of cAMP-dependent protein kinase but independent of cap-ribose methylation of mRNA.
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PMID:Two distinct mechanisms control the accumulation of cyclin B1 and Mos in Xenopus oocytes in response to progesterone. 1051 66

Increasing evidence has demonstrated striking sex differences in the pathophysiology of and outcome after acute neurological injury. Lesser susceptibility to postischemic and posttraumatic brain injury in females has been observed in experimental models. Additional evidence suggests this sex difference extends to humans as well. The greater neuroprotection afforded to females is likely due to the effects of circulating estrogens and progestins. In fact, exogenous administration of both hormones has been shown to improve outcome after cerebral ischemia and traumatic brain injury in experimental models. The neuroprotection provided by periinjury administration of these hormones extends to males as well. The mechanisms by which estrogen and progesterone provide such neuroprotection are likely multifactorial, and probably depend on the type and severity of injury as well as the type and concentration of hormone present. Both genomic and nongenomic mechanisms may be involved. Estrogen's putative effects include preservation of autoregulatory function, an antioxidant effect, reduction of A beta production and neurotoxicity, reduced excitotoxicity, increased expression of the antiapoptotic factor bcl-2, and activation of mitogen activated protein kinase pathways. It is hypothesized that several of these neuroprotective mechanisms can be linked back to estrogen's ability to act as a potent chemical (i.e., electron-donating) antioxidant. Progesterone, on the other hand, has a membrane stabilizing effect that also serves to reduce the damage caused by lipid peroxidation. In addition, it may also provide neuroprotection by suppressing neuronal hyperexcitability. The following review will discuss experimental and clinical evidence for sex differences in outcome after acute brain trauma and stroke, review the evidence implicating estrogens and progestins as mediators of this neuroprotection following acute neurological injury, and finally, address the specific mechanisms by which these hormones may protect the brain following acute neurological injury.
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PMID:Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. 1083 57

Progesterone, which is required to support human gestation, is derived initially from the corpus luteum and subsequently from the placenta. The rate-limiting step in progesterone synthesis is the delivery of cholesterol to the mitochondrial cholesterol side-chain cleavage system. The steroidogenic acute regulatory protein (StAR) mediates this process in the corpus luteum, whereas in the placenta, which does not express StAR, a StAR homologue, MLN64, may accomplish this function. StAR expression is regulated in the ovary at the transcriptional level by a cAMP-activated signal transduction system and StAR activity is also increased acutely by protein kinase A-mediated phosphorylation. These long-term (transcriptional) and short-term (post-translational, that is, phosphorylation) mechanisms govern luteal steroidogenic activity. The StAR protein has two key functional domains. The StAR C-terminal domain increases cholesterol movement to cytochrome P450scc by promoting sterol desorption from the sterol-rich outer mitochondrial membrane, driving it to the relatively sterol-poor inner membrane. The N-terminal domain mitochondrial targeting sequence directs the StAR protein to the mitochondria.
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PMID:Providing progesterone for pregnancy: control of cholesterol flux to the side-chain cleavage system. 1088 29

Quiescent full-grown Xenopus oocytes remain arrested at the G(2)/M border of meiosis I until exposed to progesterone, their natural mitogen. Progesterone triggers rapid, nontranscriptional responses that lead to the translational activation of stored mRNAs, resumption of the meiotic cell cycles, and maturation of the oocyte into a fertilizable egg. It has long been presumed that progesterone activates the oocyte through a novel nontranscriptional signaling receptor. Here, we provide evidence that a conventional transcriptional progesterone receptor cloned from Xenopus oocytes, XPR-1, is required for oocyte activation. Overexpression of XPR-1 through mRNA injection increases sensitivity to progesterone and accelerates progesterone-activated cell cycle reentry. Injection of XPR-1 antisense oligonucleotides blocks the ability of oocytes to respond to progesterone; these oocytes are rescued by subsequent injection of XPR-1 or the human progesterone receptor PR-B. Antisense-treated oocytes can be activated in response to inhibition of protein kinase A, one of the earliest known changes occurring downstream of progesterone stimulation. These results argue that the conventional progesterone receptor also functions as the signaling receptor that is responsible for the rapid nontranscriptional activation of frog oocytes.
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PMID:Identification of XPR-1, a progesterone receptor required for Xenopus oocyte activation. 1113 41

The purpose of this study was to analyze the mechanism of transcriptional inhibition of human chorionic gonadotropin-alpha (hCGalpha) gene by progesterone in trophoblast cells. We stably transfected -290 bp hCGalpha promoter-CAT constructs (-290halphaCAT) into Rcho-1 cells and monitored the promoter activities. Differentiation-dependent activation of -290 bp hCGalpha promoter containing a tandem repeat of cAMP response element (CRE) was inhibited by progesterone in a dose-dependent manner. To further analyze the mechanism of the progesterone action, Rcho-1 cells stably transfected with -290halphaCAT were treated with forskolin in the presence of progesterone. Progesterone inhibited forskolin-induced transcriptional activation of hCGalpha gene. Moreover, progesterone inhibited forskolin-induced transcriptional activation of CRE-CRE-tk-CAT. These results suggest that progesterone may inhibit cAMP-induced transcriptional activation of hCGalpha gene through CRE. Although progesterone did not alter the amount of CRE-binding protein (CREB), which is a main transcriptional factor bound to CRE(s) on hCGalpha promoter, progesterone abolished forskolin-induced CREB phosphorylation. In addition, pretreatment with progesterone abolished forskolin-induced activation of nuclear protein kinase A (PKA). In conclusion, progesterone inhibits hCGalpha gene transcription, at least in part, via the CRE region by inhibiting CREB phosphorylation through PKA pathway in trophoblast cells.
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PMID:Progesterone inhibits transcriptional activation of human chorionic gonadotropin-alpha gene through protein kinase A pathway in trophoblast cells. 1151 56

Progesterone is a critical steroid hormone that controls cell proliferation and differentiation in the female reproductive tract. Progesterone acts through two nuclear receptor isoforms, progesterone receptors A and B (PRA and PRB, respectively), each with unique cellular effects. Loss of PRB has recently been linked to the development of poorly differentiated endometrial tumors, a lethal form of cancer. To study the molecular effects of progesterone, progesterone receptors were introduced into Hec50co endometrial cancer cells by adenoviral vectors encoding either PRA or PRB. Progesterone induced the cyclin-dependent kinase inhibitors p21 and p27, thereby significantly reducing the percentage of proliferating cells. Cancer cell invasion was also markedly inhibited as measured by Matrigel invasion studies. Similarly, a differentiated, secretory phenotype was induced by progesterone in cells expressing PRB. However, replicative senescence was induced by progesterone only in cells expressing PRA. Expression array analysis followed by confirmatory semiquantitative reverse transcription-PCR experiments demonstrated a significant progesterone-dependent inhibition of expression of a cadre of cellular adhesion molecules, including fibronectin, integrin alpha3, integrin beta1, integrin beta3, and cadherin 6. The level of down-regulation of adhesion molecule expression was significantly greater in the presence of the B isoform, demonstrating that progesterone acts principally through B receptors to inhibit cancer cell invasiveness modulated by adhesion molecules.
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PMID:Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. 1183 May 47

Progesterone induces G2-arrested Xenopus oocytes to develop into fertilizable eggs in a process called meiotic maturation. Protein kinase A (PKA), the cAMP-dependent protein kinase, has long been known to be a potent inhibitor of meiotic maturation, but little information is available on how PKA functions. We have cloned two Xenopus PKA catalytic subunit isoforms, XPKAalpha and XPKAbeta. These proteins are 89% identical and both inhibit progesterone-induced meiotic maturation when overexpressed at low levels, suggesting that PKA activity is tightly regulated in the oocyte. Unexpectedly, catalytically inactive XPKA mutants are able to block progesterone-induced maturation as efficiently as the wild-type active XPKA. These mutants also block meiotic maturation induced by Mos, but are less efficient at inhibiting Cdc25C-induced maturation. Our results indicate that PKA can inhibit meiotic maturation by a novel mechanism, which does not require its kinase activity and is also independent of binding to the PKA regulatory subunits.
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PMID:Inhibition of Xenopus oocyte meiotic maturation by catalytically inactive protein kinase A. 1190 61


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