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)

This is a progress report of an attempt to deconstruct the signaling network underlying cell cycle control in the mouse Y1 adrenocortical cell line, aiming to uncover ACTH growth regulatory pathways. Y1 adrenocortical tumor cells possess amplified and overexpressed c-Ki-ras proto-oncogene. Despite this oncogenic lesion, Y1 cells retain tight regulatory mechanisms of cell cycle control typified by the sequential events comprising the mitogenic response triggered by FGF2 in G0/G1-arrested Y1 cells: 1) activation of ERK1/2 and PI3K, by 5 minutes; 2) induction of c-Fos and c-Myc proteins by 2 hours; 3) induction of cyclin D1 protein by 5 hours; 4) phosphorylation of Rb protein between 6 and 8 hours; 5) onset of DNA synthesis by 8-9 hours. In this cell line, ACTH-receptor (ACTH-R) activates contradictory pathways of growth regulation. First, ACTH coordinately induces fos and jun gene families via activation of both ERK1/2 and cAMP/PKA pathways, resembling a mitogen. Second, ACTH-R triggers cAMP/PKA-mediated antimitogenic mechanisms comprised of Akt/PKB dephosphorylation/deactivation, c-Myc protein degradation, and p27(Kip1) protein induction. Induction of cyclin D1 depends on activation of both ERK1/2 and PI3K, but is not affected by ACTH action. As a consequence, ACTH antagonizes FGF2 mitogenic activity but ectopic expression of the c-Myc protein (via MycER fusion protein) is sufficient to abrogate this ACTH antagonistic effect over FGF2 mitogenic activity. Ectopic expression of both c-Myc and cyclin D1 is not sufficient to drive G0/G1-arrested Y1 cells into S phase, but when the sustained expression of these two proteins is complemented by ACTH treatment it promotes G1 phase progression and DNA synthesis initiation. In conclusion, ACTH-receptor lacks signaling potential sufficient to initiate a mitogenic response in Y1 adrenocortical cells and, therefore, cannot substitute for bona fide mitogens like FGF2.
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PMID:Deconstructing the molecular mechanisms of cell cycle control in a mouse adrenocortical cell line: roles of ACTH. 1276 42

We have uncovered a functional bone morphogenetic protein (BMP) and activin system complete with ligands (BMP-6 and activin betaA/betaB), receptors (activin receptor-like kinase receptors 2, 3, and 4; activin type-II receptor; and BMP type-II receptor), and the binding protein follistatin in the human adrenocortical cell line H295R. Administration of activin and BMP-6 to cultures of H295R cells caused concentration-responsive increases in aldosterone production. The mRNA levels of steroidogenic acute regulatory protein or P450 steroid side-chain cleavage enzyme, the rate-limiting steps of adrenocortical steroidogenesis, were enhanced by activin and BMP-6. Activin and BMP-6 also activated the transcription of steroidogenic acute regulatory protein as well as the late-step steriodogenic enzyme CYP11B2. Activin enhanced ACTH-, forskolin-, or dibutyryl-cAMP- but not angiotensin II (Ang II)-induced aldosterone production, whereas BMP-6 specifically augmented Ang II-induced aldosterone production. Activin and ACTH but not BMP-6 increased cAMP production. Follistatin, which inhibits activin actions by binding, suppressed basal and ACTH-induced aldosterone secretion but failed to affect the Ang II-induced aldosterone level. Furthermore, MAPK signaling appeared to be involved in aldosterone production induced by Ang II and BMP-6 because an inhibitor of MAPK activation, U0126, reduced the level of aldosterone synthesis stimulated by Ang II and BMP-6 but not activin. In addition, Ang II reduced the expression levels of BMP-6 but increased that of activin betaB, whereas ACTH had no effect on these levels. Collectively, the present data suggest that activin acts to regulate adrenal aldosterone synthesis predominantly by modulating the ACTH-cAMP-protein kinase A signaling cascade, whereas BMP-6 works primarily by modulating the Ang II-MAPK cascade in human adrenal cortex in an autocrine/paracrine fashion.
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PMID:Novel action of activin and bone morphogenetic protein in regulating aldosterone production by human adrenocortical cells. 1459 55

Novel neurotrophin-1/B cell stimulating factor-3 (NNT-1/BSF-3) is a gp130 cytokine potently stimulating corticotroph proopiomelanocortin gene expression and ACTH secretion by a Janus kinase-signal transducer and activator of transcription (JAK-STAT)-dependent mechanism. In the current study, we examined the regulation of NNT-1/BSF-3 mRNA expression in murine pituitary folliculostellate TtT/GF cells using Northern blot technique. A 5- to 9-fold and a 4- to 7-fold induction in NNT-1/BSF-3 mRNA expression was observed between 2 and 6 h stimulation with the protein kinase C (PKC) stimulus phorbol-12-myristate-13-acetate (100 nm) and the protein kinase A (PKA) stimulus Bu(2)cAMP (5 mm), respectively. Pituitary adenylate cyclase-activating polypeptide (PACAP-38, 50 nm) and vasoactive intestinal peptide (VIP, 50 nm) also stimulated NNT-1/BSF-3 mRNA expression 5- to 9-fold between 2 and 6 h. Preincubation with PKC and PKA inhibitors such as H-7 (20 microm), GF109203X (50 microm), and H-89 (50 microm) decreased the stimulatory effects of PACAP and VIP. Both PACAP-38 and VIP also rapidly induced ERK1/2 phosphorylation and their stimulatory effect on NNT-1/BSF-3 mRNA expression was reduced by the MAPK kinase/ERK kinase (MEK) inhibitor U0126 (10 microm). Dexamethasone (10(-7) m) was a potent inhibitor of phorbol-12-myristate-13-acetate-induced NNT-1/BSF-3 expression. RT-PCR analysis demonstrated TtT/GF cells to express the short and the hop variant but not the hip variant of the PACAP-1 receptor (PAC1-R). In addition, TtT/GF cells express the VIP/PACAP-2 receptor (VPAC2-R). In summary, NNT-1/BSF-3 is expressed in pituitary folliculostellate TtT/GF cells and induced by PKC-, PKA-, and ERK1/2-dependent mechanisms. The novel gp130 cytokine NNT-1/BSF-3 derived from folliculostellate cells might act as a paracrine neuroimmunoendocrine modulator of pituitary corticotroph function.
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PMID:Expression of novel neurotrophin-1/B-cell stimulating factor-3 (NNT-1/BSF-3) in murine pituitary folliculostellate TtT/GF cells: pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide-induced stimulation of NNT-1/BSF-3 is mediated by protein kinase A, protein kinase C, and extracellular-signal-regulated kinase1/2 pathways. 1460 1

Tandospirone, an azapirone, is a selective serotonin(1A) (5-HT(1A)) receptor agonist. The effects of tandospirone on plasma hormones and on mitogen-activated protein (MAP) kinase activity in the brain of male rats were studied. Tandospirone produced a time- and dose-dependent increase in plasma levels of oxytocin, adrenocorticotropin (ACTH), corticosterone, and prolactin. The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin, ACTH, and prolactin levels was 1.0 mg/kg (s.c.), while the minimal dose for corticosterone release was 3.0 mg/kg (s.c.). The ED(50) of tandospirone was 1.3 mg/kg for oxytocin, 1.2 mg/kg for ACTH, 3.0 mg/kg for corticosterone, and 0.24 mg/kg for prolactin. Pretreatment with the specific 5-HT(1A) receptor antagonist WAY 100,635 (0.3 mg/kg, s.c.) completely blocked the effects of tandospirone on plasma levels of oxytocin, ACTH, and corticosterone but shifted the dose-response curve for prolactin to the right. Tandospirone injection (10 mg/kg, s.c.) stimulated the MAP kinase signaling cascade, specifically the phosphorylation of p42/44 extracellular signal-regulated kinase (ERK). Western blot analysis revealed a significant increase in phosphorylated ERK (p-ERK) levels in the hypothalamic paraventricular nucleus (PVN) as well as the dorsal raphe nucleus 5 min following tandospirone injection. These increases were blocked by pretreatment with WAY 100,635 (0.3 mg/kg). The results are the first evidence that systemic 5-HT(1A) receptor agonist administration produces a rapid increase in p-ERK levels in vivo, providing further insight into the signaling mechanisms of the 5-HT(1A) receptor.
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PMID:Tandospirone activates neuroendocrine and ERK (MAP kinase) signaling pathways specifically through 5-HT1A receptor mechanisms in vivo. 1565 73

ACTH is known to act through the activation of cAMP/PKA in adrenocortical cells, but it has been suggested that it could also act via other pathways such as the ERK 1/2 cascade. To determine the effects of ACTH administration at sequential time points on the activation of ERKs 1/2, groups of rats (n = 6/group) were subjected to i.p. injections of either ACTH (Synacthen Depot-0.2 mg/Kg), or saline (Ct). The animals were sacrificed and the adrenal glands collected at different timings after ACTH injection (2 h, 18 h and 24 h). Two additional groups were injected daily until sacrifice (3 days and 15 days). Blood was collected for analysis and the adrenals were used for immunohistochemistry or Western Blot (WB) analysis. Immunoreactivity was scored by counting the mean number of zonae fasciculata (ZF) and reticularis (ZR) positive cells/section (mean +/- SEM). Adrenal weight was increased by ACTH in comparison with Ct. Corticosterone levels, as expected, were higher in ACTH treated animals than in Ct. The number of pERK positive cells increased in a time-dependent manner until 3d, and declined although not significantly in the 15 days animals (Control--48.13 +/- 9.0; ACTH 2 h--125.93 +/- 14.5; ACTH 18 h-139.46 +/- 10.0; ACTH 24 h--185.28 +/- 13.3; ACTH 3 days--198.47 +/- 18.6; ACTH 15 days--158.58 +/- 15.1). Comparable results were obtained with WB analysis. Our data shows that ACTH induces the activation of the MAPK/ERKs 1/2 cascade, especially in the ZF, consistent with this zone being more responsive to ACTH.
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PMID:ACTH modulates ERK phosphorylation in the adrenal gland in a time-dependent manner. 1566 9

Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that has emerged as a critical mediator of endocrine function at multiple levels of the hypothalamic-pituitary-steroidogenic axis. Within the adrenal cortex, ACTH-dependent transcriptional responses, including transcriptional activation of several key steroidogenic enzymes within the steroid biosynthetic pathway, are largely dependent upon SF-1 action. The absence of a bona fide endogenous eukaryotic ligand for SF-1 suggests that signaling pathway activation downstream of the melanocortin 2 receptor (Mc2r) modulates this transcriptional response. We have used the chromatin immunoprecipitation assay to examine the temporal formation of ACTH-dependent transcription complexes on the Mc2r gene promoter. In parallel, ACTH-dependent signaling events were examined in an attempt to correlate transcriptional events with the upstream activation of signaling pathways. Our results demonstrate that ACTH-dependent signaling cascades modulate the temporal dynamics of SF-1-dependent complex assembly on the Mc2r promoter. Strikingly, the pattern of SF-1 recruitment and the subsequent attainment of active rounds of transcription support a kinetic model of SF-1 transcriptional activation, a model originally established in the context of ligand-dependent transcription by several classical nuclear hormone receptors. An assessment of the major ACTH-dependent signaling pathways highlights pivotal roles for the MAPK as well as the cAMP-dependent protein kinase A pathway in the entrainment of SF-1-mediated transcriptional events. In addition, the current study demonstrates that specific enzymatic activities are capable of regulating distinct facets of a highly ordered transcriptional response.
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PMID:Adrenocorticotropic hormone-mediated signaling cascades coordinate a cyclic pattern of steroidogenic factor 1-dependent transcriptional activation. 1610 36

Pituitary adenomas are neuroendocrine tumors that produce different endocrine and metabolic alterations, including hyperprolactinemia, acromegaly and Cushing's disease. These different clinical features of pituitary tumors are the result of the overproduction of hormones produced by the different pituitary cell types. Recent advances in the understanding of the signaling pathways that control hormone production in pituitary cells provide a source of potential therapeutic targets. In ACTH-secreting cells, the mechanisms that control hormone biosynthesis have been clarified to a great extent, indicating a number of protein kinases and ligand-activated nuclear receptors as targets for experimental drugs. ACTH production requires the activation of signal transduction through the PKA, the MAPK and the CamK pathways. These pathways activate nuclear receptors, including Nur and PPAR gamma. The inhibition of these kinases and nuclear receptors has been shown to produce therapeutic effects in mouse models of Cushing's syndrome. On the other hand, the signaling pathways that control prolactin and growth hormone production also have potential targets. It has been recently shown that SMAD proteins activated by growth factors of the TGF beta and BMP family interact with estrogen receptors to stimulate the proliferation of prolactin and growth hormone-secreting cells. Cytokines that bind to the membrane protein gp130 also stimulate the proliferation of these cells. The inhibition of both of these pathways results in the decrease of tumor growth in animal models of prolactinoma. Therefore, the study of signaling pathways that control hormone production and proliferation is a good source of candidate targets in pituitary tumors.
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PMID:Signaling processes in tumoral neuroendocrine pituitary cells as potential targets for therapeutic drugs. 1617 87

The adrenal gland of the rat is continuously regenerated through proliferation of a stem cell population in the outer part of the gland. To clarify the location of proliferative events within the adrenal gland, and the factors that stimulate them, rat adrenal capsule preparations, consisting of capsule, zona glomerulosa (ZG) and the outer zona fasciculata (ZF) were maintained in vitro under different conditions of stimulation, for varying periods. Sites of proliferation were identified by 5-bromo-2'-deoxy-uridine (BrdU) staining, and the distribution of classical MAP kinase (MAPK) family members, extracellular signal-regulated kinase (ERK) 1 and 2, immunoreactivity was determined using immunocytochemistry. BrdU staining was limited to the outer glomerulosa and the capsule, where it was enhanced by angiotensin II, but not by a high potassium ion concentration nor by ACTH. In contrast, ERK1/2 immunoreactivity was distributed throughout the ZG and in the medulla, with none detectable in the ZF and reticularis. Furthermore, angiotensin II, potassium ions and ACTH were all shown to induce ERK1 and ERK2 phosphorylation in the ZG. Treatment of adrenal capsule tissue with the specific MAPK kinase inhibitor PD98059 revealed inhibition of ERK1/2 phosphorylation, but no effect on angiotensin II-induced aldosterone secretion. Although the distribution and activation of the MAPK pathway suggest a link with proliferation, the findings clearly designated only the outer part of the glomerulosa and capsule as a potential stem cell population. Further functions should be sought for the apparently silent major part of the glomerulosa.
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PMID:Distribution of extracellular signal-regulated protein kinases 1 and 2 in the rat adrenal and their activation by angiotensin II. 1621 50

Aldosterone production in zona glomerulosa (ZG) cells of adrenal glands is regulated by various extracellular stimuli (K(+), ANG II, ACTH) that all converge on two major intracellular signaling pathways: an increase in cAMP production and calcium (Ca(2+)) mobilization. However, molecular events downstream of the increase in intracellular cAMP and Ca(2+) content are controversial and far from being completely resolved. Here, we found that Ca(2+)/calmodulin-dependent protein kinases (CaMKs) play a predominant role in the regulation of aldosterone production stimulated by ANG II, ACTH, and cAMP. The specific CaMK inhibitor KN93 strongly reduced ANG II-, ACTH-, and cAMP-stimulated aldosterone production. In in vitro kinase assays and intact cells, we could show that cAMP-induced activation of CaMK, using the adenylate cyclase activator forskolin or the cAMP-analog Sp-5,6-DCI-cBIMPS (cBIMPS), was not mediated by PKA. Activation of the recently identified cAMP target protein Epac (exchange protein directly activated by cAMP) by 8-pCPT-2'-O-Me-cAMP had no effect on CaMK activity and aldosterone production. Furthermore, we provide evidence that cAMP effects in ZG cells do not involve Ca(2+) or MAPK signaling. Our results suggest that ZG cells, in addition to PKA and Epac/Rap proteins, contain other as yet unidentified cAMP mediator(s) involved in regulating CaMK activity and aldosterone secretion.
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PMID:Regulation of aldosterone production from zona glomerulosa cells by ANG II and cAMP: evidence for PKA-independent activation of CaMK by cAMP. 1621 70

In this study, DNA synthesis, phosphorylation of ERK1/2 and CREB proteins, as well as induction of c-Fos protein, were examined in rat adrenocortical, glomerulosa and fasciculata/reticularis cells, as well as in the Y1 cell line. We found that FGF2 was mitogenic only in glomerulosa cells and although ACTH did not activate ERK1/2, it did activate CREB protein, indicating efficient transduction of signals initiated in the ACTH receptors of rat adrenocortical cells. The FGF2 activated ERK1/2 in rat adrenal cells by a mechanism that might be modulated by upstream PKA pathway phosphorylation of MEK and despite the nonmitogenic effect of ACTH on rat adrenal cells it effectively induces c-Fos protein. The results presented herein describe distinct differences between the ACTH and FGF2 signal transduction mechanisms seen in adrenocortical cells and those observed in the Y1 cell line, indicating that, in vitro, ACTH blockage of the mitogenic effect occurs in normal adrenal cells after induction of c-Fos protein.
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PMID:Differences between the growth regulatory pathways in primary rat adrenal cells and mouse tumor cell line. 1628 4


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