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

---

Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin-II (AII), which stimulates steroidogenesis in bovine adrenocortical (BAC) cells through the phosphoinositides pathway, activates p42-p44 mitogen-activated protein kinases (MAPKs) after 5 min of treatment (EC50 = 0.1 nM). This activation is 1) completely inhibited by the AII receptor AT1 subtype antagonist Dup 753 (10 microM), but unaffected by the AT2 antagonist PD 123177; 2) not reproduced by the AT2 agonist CGP 42112A; 3) insensitive to pretreatment with pertussis toxin; and 4) abolished by a 48-h preexposure of the cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA; 1 microM), which down-regulates protein kinase-C activity. Fibroblast growth factor-2, a potent mitogen for BAC cells, which acts through its tyrosine kinase receptor, also activates MAPK (EC50 = 0.3 in a TPA-insensitive manner, while exhibiting no detectable effect on BAC cell steroidogenesis. In contrast, ACTH, which stimulates steroidogenesis via cAMP and inhibits BAC cell proliferation, does not stimulate MAPK. Indeed, ACTH completely blocks (IC50 = 0.01 nM) the stimulation of MAPK by AII, fibroblast growth factor-2, or TPA. Therefore, bovine adrenocortical cells provide an example of positive and negative hormonal regulation of MAPK activity through a cross-talk between the inositide-, cAMP-, and growth factor-activated tyrosine kinase pathways.
...
PMID:Hormonal regulation of mitogen-activated protein kinase activity in bovine adrenocortical cells: cross-talk between phosphoinositides, adenosine 3',5'-monophosphate, and tyrosine kinase receptor pathways. 786 5

A broad array of stressors induce ACTH release from the anterior pituitary, with consequent stimulation of the adrenal cortex and release of glucocorticoids critical for survival of the animal. ACTH stimulates adrenocortical gene expression in vivo and inhibits adrenocortical cell proliferation. Binding of ACTH to its G-protein-coupled receptor stimulates the production of cAMP and activation of the protein kinase A pathway. The stress-activated protein kinases (SAPKs) (or c-Jun N-terminal kinases) and the extracellular signal-regulated kinases (ERKs) are members of the mitogen-activated protein kinase family of serine/threonine kinases, which have recently been implicated in G-protein-coupled receptor intracellular signaling. The SAPKs are preferentially induced by osmotic stress and UV light, whereas the ERKs are preferentially induced by growth factors and proliferative signals in cultured cells. In these studies, ACTH stimulated SAPK activity 3-4-fold both in the adrenal cortex in vivo and in the Y1 adrenocortical cell line. 12-O-Tetradecanoylphorbol-13-acetate but not cAMP induced SAPK activity in Y1 cells. The isoquinolinesulfonamide inhibitors H-8 and H-89 blocked ACTH induction of SAPK activity at protein kinase C inhibitory doses but not at protein kinase A inhibitory doses. The calcium chelating agent EGTA inhibited ACTH-induced SAPK activity and the calcium ionophore A23187 induced SAPK activity 3-fold. In contrast with the induction of SAPK by ACTH, ERK activity was inhibited in the adrenal cortex in vivo and in Y1 adrenal cells. Together these findings suggest that ACTH induces SAPK activity through a PKC and Ca+2-dependent pathway. The induction of SAPK and inhibition of ERK by ACTH in vivo may preferentially regulate target genes involved in the adrenocortical stress responses in the whole animal.
...
PMID:Adrenocorticotropin induction of stress-activated protein kinase in the adrenal cortex in vivo. 924 78

ACTH treatment of Y1 adrenocortical cells induces the synthesis of Nur77, an orphan nuclear receptor that can act as a potent transactivator for such genes as 21-hydroxylase (CYP21). Nur77 has thus been proposed to be a mediator of ACTH action in activating the expression of genes that encode steroidogenic enzymes. Here we show that ACTH regulates the activity of Nur77 at the level of phosphorylation. ACTH induces the synthesis of transcriptionally active, DNA-binding Nur77 that is unphosphorylated at Ser354, which resides within the DNA-binding domain. By contrast, the Nur77 population that is constitutively present in Y1 cells is phosphorylated at Ser354 and does not bind DNA. Substitutions of Ser354 with negatively charged amino acids, such as Asp or Glu, dramatically decreased Nur77 DNA-binding and trans-activation activities, whereas mutation to the neutral Ala had no effect. Aside from phosphorylation within the DNA-binding domain, ACTH treatment does not induce modifications in the N- and C-terminal domains of Nur77 that significantly affect activity. Although the specific kinases that phosphorylate Nur77 in vivo are not known, the mitogen-activated protein kinase/pp90RSK pathway is not critical to Nur77 regulation. We propose that ACTH treatment of Y1 cells results in modulation of the activities of both kinases and phosphatases, which, in turn, regulate the activities of such transcription factors as Nur77.
...
PMID:Adrenocorticotropic hormone regulates the activities of the orphan nuclear receptor Nur77 through modulation of phosphorylation. 932 22

We studied a patient with food-induced, ACTH-independent, Cushing's syndrome and a unilateral adrenocortical adenoma. In vivo cortisol secretion was stimulated by mixed, glucidic, lipidic, or proteic meals. Plasma ACTH levels were undetectable, but iv injection of ACTH stimulated cortisol secretion. Unilateral adrenalectomy was followed by hypocortisolism with loss of steroidogenic responses to both food and ACTH. In vitro, cortisol secretion by isolated tumor cells was stimulated by the gut hormone gastric inhibitory polypeptide (GIP) and ACTH, but not by another gut hormone, glucagon-like peptide-1 (GLP-1). Both peptides stimulated the production of cAMP but not of inositol 1,4,5-trisphosphate. In quiescent cells, GIP and ACTH stimulated [3H]thymidine incorporation and p42-p44 mitogen-activated protein kinase activity. GIP receptor messenger ribonucleic acid (RNA), assessed by RT-PCR, was highly expressed in the tumor, whereas it was undetectable in the adjacent hypotrophic adrenal tissue, in two adrenal tumors responsible for food-independent Cushing's syndrome, and in two hyperplastic adrenals associated with ACTH hypersecretion. In situ hybridization demonstrated that expression of GIP receptor RNA was confined to the adrenocortical tumor cells. Low levels of ACTH receptor messenger RNA were also detectable in the tumor. We conclude that abnormal expression of the GIP receptor allows adrenocortical cells to respond to food intake with an increase in cAMP that may participate in the stimulation of both cortisol secretion and proliferation of the tumor cells.
...
PMID:Cushing's syndrome due to a gastric inhibitory polypeptide-dependent adrenal adenoma: insights into hormonal control of adrenocortical tumorigenesis. 974 16

ACTH, Angiotensin II (Ang II) and Vasopressin (AVP) are among the well known regulators of aldosterone secretion and also have a trophic action on the adrenal gland. According to classic studies, Ang II and AVP activate phospholipase C (PLC), diacylglycerol (DAG) and inositol phosphate (InsPs) production whereas ACTH activates cAMP production. However, our data indicate that the three peptides are able to induce a time-dependent increase in the level of Tyr-phosphorylation of several proteins. Western Blot analysis indicates a biphasic activation of Tyr-phosphorylation by AVP, with a peak at 30 s and a second one at 15 min incubation. Ang II induced a rapid (2 min) and sustained activation of Tyr-phosphorylation, while ACTH induced a progressive time course with a plateau reached at 15 min. Ang II and AVP also increased phosphorylation of p42mapk and p44mapk, while ACTH did not affect MAPK activity. Moreover, pre-incubation of the cells with genistein (Tyr-kinase inhibitor) and PD 098059 (a MAPK inhibitor) did not affect InsPs production or aldosterone secretion induced by Ang II or AVP. These results suggest that the MAPK pathway is involved in the control of cell growth rather than aldosterone secretion.
...
PMID:Involvement of tyrosine phosphorylation and MAPK activation in the mechanism of action of ACTH, angiotensin II and vasopressin. 988 17

We studied in vitro an adrenal tumor responsible for food-dependent, ACTH independent, Cushing's's syndrome. Cortisol secretion by isolated tumor cells was stimulated by GIP and ACTH, but not by the gut hormone glucagon-like peptide-1 (GLP-1). Both GIP and ACTH stimulated production of cAMP but not inositol 1,4,5-trisphosphate IP3). In quiescent tumor cells, GIP and ACTH stimulated [3H]-thymidine incorporation and p42-p44 MAP kinase activity. In normal human adrenocortical cells cortisol secretion and [3H]-thymidine incorporation were stimulated by ACTH but not by GIP. GIP receptor mRNA, assessed by RT-PCR, was highly expressed in the tumor, but undetectable in the adjacent hypotrophic adrenal tissue, in a normal adrenal, in two adrenal tumors responsible for food-independent Cushing's syndrome and in two hyperplastic adrenals associated with ACTH hypersecretion. Low levels of ACTH receptor mRNA were also detectable in the tumor. We conclude that abnormal expression of the GIP receptor allows adrenocortical cells to respond to food intake with an increase of cAMP that may participate in stimulation of both cortisol secretion and proliferation of the tumor cells.
...
PMID:Gastric inhibitory polypeptide (GIP) stimulates cortisol secretion, cAMP production and DNA synthesis in an adrenal adenoma responsible for food-dependent Cushing's syndrome. 988 86

FGF2 elicits a strong mitogenic response in the mouse Y-1 adrenocortical tumor cell line, that includes a rapid and transient activation of the ERK-MAPK cascade and induction of the c-Fos protein. ACTH, itself a very weak mitogen, blocks the mitogenic response effect of FGF2 in the early and middle G1 phase, keeping both ERK-MAPK activation and c-Fos induction at maximal levels. Probing the mitogenic response of Y-1 cells to FGF2 with ACTH is likely to uncover reactions underlying the effects of this hormone on adrenocortical cell growth.
...
PMID:Control of the adrenocortical cell cycle: interaction between FGF2 and ACTH. 1045 42

In the present study, we report that ACTH induces a transient chloride current. The lack of correlation between ACTH-induced cAMP production and amplitude of the Cl- current, as well as the absence of stimulation by forskolin or 8Br-cAMP indicated that the ACTH-induced current was not cAMP-dependent. We explored the possibility that one or several elements of the Ras/Raf MAPK cascade were involved. Indeed, we found that ACTH at 10(-10) M induced activation of Ras. Inhibition of the current by QEHA peptide, a Gbetagamma sequestrant, demonstrated that Gbetagamma subunits transduced the message. Blockage of the Ras activation using an inhibitor of farnesyl transferase (BZA-5B) or the monoclonal antibody H-Ras(259) abrogated the current. Moreover, the addition of Ras-GTPyS in the pipette medium gave rise to the Cl- current. Treatment of the cells with BZA decreased the aldosterone secretion induced by 10(-10) M ACTH but not that induced by 10(-8) M ACTH, confirming the involvement of Ras in steroid secretion. We conclude that ACTH triggers a Cl- current through the activation of the Ras protein by Gbetagamma subunits. This current, activated at physiological ACTH concentrations (1 to 100 pM) where cAMP production is very low, could play a significant role in aldosterone production.
...
PMID:A Ras-dependent chloride current activated by adrenocorticotropin in rat adrenal zona glomerulosa cells. 1065 Sep 50

The effect of adrenomedullin (ADM) on the proliferative activity of the rat adrenal cortex has been investigated in vivo, using an in situ perfusion technique of the intact left gland. ADM and other chemicals were dissolved in the perfusion medium, and the perfusion was continued for 180 min. ADM infusion concentration dependently increased the mitotic index and [3H]thymidine incorporation into DNA in the zona glomerulosa (ZG; the maximal effective concentration was 10(-8) M), but not in inner adrenocortical layers, where basal proliferative activity was negligible. The effect of 10(-8) M ADM was equipotently counteracted by both the calcitonin gene-related peptide (CGRP) type 1 receptor antagonist CGRP-(8-37) and ADM-(22-52). The adenylate cyclase inhibitor SQ-22536 (10(-4) M), the cAMP blocker Rp-cAMP-S (10(-3) M), and the protein kinase A inhibitor H-89 (10(-5) M), although counteracting the ZG proliferogenic action of 10(-9) M ACTH, did not affect the 10(-8) M ADM-elicited increase in ZG DNA synthesis. Similar results were obtained using the phospholipase C inhibitor U-73122 (10(-5) M), the inositol-1,4,5-trisphosphate antagonist D,L-myo-inositol-1,4,5-trisphosphothiate (10(-4) M), and the protein kinase C inhibitor calphostin C (10(-5) M), which, however, significantly inhibited the ZG proliferogenic effect of 10(-9) M angiotensin II. The growth-promoting action of 10(-8) M ADM was not affected by the phospholipase A2 inhibitor AACOCF3 (10(-5) M), the cyclooxygenase (COX) inhibitor indomethacin (10(-5) M), or the mixed COX/lipoxygenase inhibitor phenidone (10(-5) M). In contrast, the ZG proliferogenic effect of 10(-8) M ADM was abolished by either the tyrosine kinase (TK) inhibitor tyrphostin-23 (10(-5) M) or the mitogen-activated protein kinase (MAPK) antagonists PD-98059 and U0216 (10(-4) M). ADM (10(-8) M) stimulated TK and p42/p44 MAPK activity in dispersed ZG, but not ZF, cells, and the effect was reversed by either 10(-6) M CGRP-(8-37) and ADM-(22-52) or preincubation with 10(-5) M tyrphostin-23. Collectively, our findings indicate that 1) ADM stimulates cell proliferation in the rat ZG, through CGRP-(8-37)- and ADM-(22-52)-sensitive receptors, probably of the CGRP1 subtype; and 2) the mitogenic effect of ADM is mediated by activation of the TK-MAPK cascade, without any involvement of the adenylate cyclase/protein kinase A-, phospholipase C/protein kinase C-, and COX- or lipoxygenase-dependent signaling pathways.
...
PMID:Adrenomedullin enhances cell proliferation and deoxyribonucleic acid synthesis in rat adrenal zona glomerulosa: receptor subtype involved and signaling mechanism. 1083 Feb 96

This article reviews recent results of studies aiming to elucidate modes of integrating signals initiated in ACTH receptors and FGF2 receptors, within the network system of signal transduction found in Y1 adrenocortical cells. These modes of signal integration should be central to the mechanisms underlying the regulation of the G0-->G1-->S transition in the adrenal cell cycle. FGF2 elicits a strong mitogenic response in G0/G1-arrested Y1 adrenocortical cells, that includes a) rapid and transient activation of extracellular signal-regulated kinases-mitogen-activated protein kinases (ERK-MAPK) (2 to 10 min), b) transcription activation of c-fos, c-jun and c-myc genes (10 to 30 min), c) induction of c-Fos and c-Myc proteins by 1 h and cyclin D1 protein by 5 h, and d) onset of DNA synthesis stimulation within 8 h. ACTH, itself a weak mitogen, interacts with FGF2 in a complex manner, blocking the FGF2 mitogenic response during the early and middle G1 phase, keeping ERK-MAPK activation and c-Fos and cyclin D1 induction at maximal levels, but post-transcriptionally inhibiting c-Myc expression. c-Fos and c-Jun proteins are mediators in both the strong and the weak mitogenic responses respectively triggered by FGF2 and ACTH. Induction of c-Fos and stimulation of DNA synthesis by ACTH are independent of PKA and are inhibited by the PKC inhibitor GF109203X. In addition, ACTH is a poor activator of ERK-MAPK, but c-Fos induction and DNA synthesis stimulation by ACTH are strongly inhibited by the inhibitor of MEK1 PD98059.
...
PMID:Proliferative signaling initiated in ACTH receptors. 1100 13


1 2 3 4 5 6 7 8 9 10 Next >>

---