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)

Heme oxygenase (HO) catalyzes the first and rate-controlling step of heme catabolism into biliverdin, iron and carbon monoxide. Three isoforms of HO have been identified so far: the inducible HO-1 and the constitutive HO-2 and HO-3. Both HO-1 and HO-2 were expressed in zona fasciculata (ZF) adrenal cells and in a mouse adrenocortical cell line (Y1). HO-1 but not HO-2 expression was upregulated by adrenocorticotropic hormone (ACTH) and accumulation of HO-1 protein correlated with an increase in HO activity in Y1 cells. ACTH induced HO-1 expression in a time- and dose-dependent manner with a maximum after 5 h of treatment and a threshold concentration of 0.1 mIU/ml. Actinomycin D and cycloheximide completely blocked the effect of ACTH on HO-1 mRNA expression whereas mRNA stability was not affected by ACTH. Permeable analogs of cAMP mimicked the effect of ACTH on HO-1 expression and ACTH induction was prevented by the protein kinase A (PKA) inhibitor H89. Steroid production was significantly increased when both HO-1 and HO-2 activities were inhibited by Sn-protoporphyrin IX (SnPPIX). The lipid peroxidation and increase in carbonyl content triggered by hydrogen peroxide was prevented by treatment of Y1 cells with bilirubin and ACTH.
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PMID:Adrenocorticotropin induces heme oxygenase-1 expression in adrenal cells. 1470 50

Nuclear receptors and their coactivators are key regulators of numerous physiological functions. GRIP1 (glucocorticoid receptor-interacting protein) is a member of the steroid receptor coactivator family. Here, we show that GRIP1 is regulated by cAMP-dependent protein kinase (PKA) that induces its degradation through the ubiquitin-proteasome pathway. GRIP1 was down-regulated in transiently transfected COS-1 cells after treatment with 8-para-chlorophenylthio-cAMP or forskolin and 3-isobutyl-1-methylxanthine and in adrenocortical Y1 cells after incubation with adrenocorticotropic hormone. Pulse-chase experiments with transiently transfected COS-1 cells demonstrated that the half-life of GRIP1 was markedly reduced in cells overexpressing the PKA catalytic subunit, suggesting that activation of PKA increases the turnover of GRIP1 protein. The proteasome inhibitors MG132 and lactacystin abolished the PKA-mediated degradation of GRIP1. Using ts20 cells, a temperature-sensitive cell line that contains a thermolabile ubiquitin-activating E1 enzyme, it was confirmed that PKA-mediated degradation of GRIP1 is dependent upon the ubiquitin-proteasome pathway. Coimmunoprecipitation studies of COS-1 cells transfected with expression vectors encoding GRIP1 and ubiquitin using anti-GRIP1 and anti-ubiquitin antibodies showed that the ubiquitination of GRIP1 was increased by overexpression of PKA. Finally, we show that PKA regulates the intracellular distribution pattern of green fluorescent protein-GRIP1 and stimulates recruitment of GRIP1 to subnuclear foci that are colocalized with the proteasome. Taken together, these data demonstrate that GRIP1 is ubiquitinated and degraded through activation of the PKA pathway. This may represent a novel regulatory mechanism whereby hormones down-regulate a nuclear receptor coactivator.
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PMID:cAMP-dependent protein kinase regulates ubiquitin-proteasome-mediated degradation and subcellular localization of the nuclear receptor coactivator GRIP1. 1534 61

Salt-inducible kinase-1 (SIK1) is phosphorylated at Ser577 by protein kinase A in adrenocorticotropic hormone-stimulated Y1 cells, and the phospho-SIK1 translocates from the nucleus to the cytoplasm. The phospho-SIK1 is dephosphorylated in the cytoplasm and re-enters the nucleus several hours later. By using green-fluorescent protein-tagged SIK1 fragments, we found that a peptide region (586-612) was responsible for the nuclear localization of SIK1. The region was named the 'RK-rich region' because of its Arg- and Lys-rich nature. SIK1s mutated in the RK-rich region were localized mainly in the cytoplasm. Because SIK1 represses cAMP-response element (CRE)-mediated transcription of steroidogenic genes, the mutants were examined for their effect on transcription. To our surprise, the cytoplasmic mutants strongly repressed the CRE-binding protein (CREB) activity, the extent of repression being similar to that of SIK1(S577A), a mutant localized exclusively in the nucleus. Several chimeras were constructed from SIK1 and from its isoform SIK2, which was localized mainly in the cytoplasm, and they were examined for intracellular localization as well as CREB-repression activity. A SIK1-derived chimera, where the RK-rich region had been replaced with the corresponding region of SIK2, was found in the cytoplasm, its CREB-modulating activity being similar to that of wild-type SIK1. On the other hand, a SIK2-derived chimera with the RK-rich region of SIK1 was localized in both the nucleus and the cytoplasm, and had a CREB-repressing activity similar to that of the wild-type SIK2. Green fluorescent protein-fused transducer of regulated CREB activity 2 (TORC2), a CREB-specific co-activator, was localized in the cytoplasm and nucleus of Y1 cells, and, after treatment with adrenocorticotropic hormone, cytoplasmic TORC2 entered the nucleus, activating CREB. The SIK1 mutants, having a strong CRE-repressing activity, completely inhibited the adrenocorticotropic hormone-induced nuclear entry of green fluorescent protein-fused TORC2. This suggests that SIK1 may regulate the intracellular movement of TORC2, and as a result modulates the CREB-dependent transcription activity. Together, these results indicate that the RK-rich region of SIK1 is important for determining the nuclear localization and attenuating CREB-repressing activity, but the degree of the nuclear localization of SIK1 itself does not necessarily reflect the degree of SIK1-mediated CREB repression.
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PMID:Salt-inducible kinase-1 represses cAMP response element-binding protein activity both in the nucleus and in the cytoplasm. 1551 Dec 37

We report here that melanocortin peptides appear to serve as the mechanism by which weakly electric fish couple socially regulated and stress-regulated brain pathways to unique changes in the intrinsic excitability and action potential waveform of excitable membranes in peripheral cells involved in communication. Gymnotiform electric fish modulate their electric organ discharges (EODs) by reshaping the electric discharges of excitable cells in the periphery. These fish show circadian enhancement of the EOD waveform. They also enhance their EOD waveforms within minutes in response to stressors and changes in the social environment, thus altering the communication value of the signal. Changes in the EOD waveform that occur within minutes result from changes in the discharges of individual electrocytes (microEODs) mediated by the cAMP/protein kinase A (PKA) pathway acting on ion channel kinetics. What activates the cAMP/PKA pathway in electrocytes has not been identified. In vivo injections of the melanocortin peptide adrenocorticotropic hormone (ACTH) increase the amplitude and duration of the electric signal waveform of the gymnotiform Brachyhypopomus pinnicaudatus over the course of 1 h. Applied to single electrocytes in vitro, ACTH increases microEOD amplitude and duration within minutes by differentially modulating the action potentials of the two excitable membranes of the electrocyte and changing the timing of these two spikes. Serotonin modulates the EOD in vivo but has no effect on the microEOD in vitro. The cAMP analog 8-bromo-cAMP mimicked the effects of ACTH, whereas inhibition of PKA by protein kinase A inhibitor 14-22 amide blocked the modulatory effects of ACTH, confirming the role of the cAMP/PKA pathway in microEOD modulation by ACTH.
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PMID:Adrenocorticotropic hormone enhances the masculinity of an electric communication signal by modulating the waveform and timing of action potentials within individual cells. 1617 44

Most adrenocortical tumors are benign, unilateral, adrenocortical adenomas that are often discovered incidentally. Adrenocortical cancer is rare. Exceptionally, adrenocortical tumors can be bilateral. Although most adrenocortical tumors occur sporadically, they may also feature in congenital and/or familial disease. The identification of germline genetic defects in familial diseases associated with adrenocortical tumors helped to define the somatic alterations in sporadic disease: for example, overexpression of insulin-like growth factor 2 and alterations at the 11p15 locus (observed in Beckwith-Wiedemann syndrome) are also found in most adrenocortical cancers. Similarly, inactivating mutations of the TP53 gene, located at 17p13 (observed in Li-Fraumeni syndrome), can also be found at the somatic level in sporadic adrenocortical cancers, as can 17p13 allelic losses. Components of the cyclic AMP signaling pathway--for example, adrenocorticotropic hormone receptors and other membrane receptors, Gs proteins and protein kinase A--can be altered to various degrees in adrenocortical tumors. More recently, gene profiling and genetic studies have shown that the Wnt-beta-catenin signaling pathway is frequently activated in adrenocortical tumors. These research findings already have profound implications for clinical management of patients with adrenocortical tumors, for example in unraveling the genetic origin of the disease in some patients, and in the development of molecular markers for diagnosis and prognosis. The new findings should also help in the development of new therapeutic options.
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PMID:Mechanisms of disease: adrenocortical tumors--molecular advances and clinical perspectives. 1708 10

Corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) are the two major regulatory peptides in the hypothalamic-pituitary-adrenal axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN) in response to stress, is secreted into the pituitary portal circulation, resulting in the release of adrenocorticotropic hormone from the anterior pituitary. AVP is synthesized in the PVN and supraoptic nucleus by various stressors. Hypothalamic 4B cells coexpress CRF and AVP. In 4B cells transfected with either a CRF or an AVP promoter-luciferase construct, forskolin increased the transcriptional activity of CRF or AVP. In the present study, we tried to determine whether pituitary adenylate cyclase-activating polypeptide (PACAP) regulates both CRF and AVP genes in the hypothalamic cells, because receptors for PACAP were expressed in the hypothalamic cells. PACAP stimulated activity of both CRF and AVP promoter via protein kinase A pathway. PACAP stimulated interleukin (IL)-6 promoter activity and the levels of IL-6 mRNA and protein. IL-6 stimulated activity of both CRF and AVP promoter in a dose-dependent manner. Finally, we found that the stimulatory effects of PACAP on both activities were significantly inhibited by treatment with anti-IL-6 monoclonal antibody. These data suggest that PACAP is involved in regulating the synthesis of IL-6 mRNA and IL-6 protein, and that the increase in endogenous IL-6 also contributes to stimulate the expression of both CRF and AVP genes. Taken together, these findings indicate that PACAP stimulates the transcription of CRF, AVP, and IL-6 genes in hypothalamic 4B cells.
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PMID:Pituitary adenylate cyclase-activating polypeptide stimulates corticotropin-releasing factor, vasopressin and interleukin-6 gene transcription in hypothalamic 4B cells. 1795 32

Adrenal tumors are common, with an estimated incidence of 7.3% in autopsy cases, while adrenocortical carcinomas (ACCs) are rare, with an estimated prevalence of 4-12 per million population. Because the prognoses for adrenocortical adenomas (ACAs) and ACCs are vastly different, it is important to be able to accurately differentiate the two tumor types. Advancement in the understanding of the pathophysiology of ACCs is essential for the development of more sensitive means of diagnosis and treatment, resulting in better clinical outcome. Adrenocortical tumors (ACTs) occur as a component of several hereditary tumor syndromes, which include the Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia 1, Carney complex, and congenital adrenal hyperplasia. The genes involved in these syndromes have also been shown to play a role in the pathogenesis of sporadic ACTs. The adrenocorticotropic hormone-cAMP-protein kinase A and Wnt pathways are also implicated in adrenocortical tumorigenesis. The aim of this review is to summarize the current knowledge on the molecular mechanisms involved in adrenocortical tumorigenesis, including results of comparative genomic hybridization, loss of heterozygosity, and microarray gene-expression profiling studies.
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PMID:Molecular markers and the pathogenesis of adrenocortical cancer. 1851 40

Bovine adrenal zona fasciculata (AZF) cells express bTREK-1 K(+) channels that set the resting membrane potential and function pivotally in the physiology of cortisol secretion. Inhibition of these K(+) channels by adrenocorticotropic hormone (ACTH) or cAMP is coupled to depolarization and Ca(2+) entry. The mechanism of ACTH and cAMP-mediated inhibition of bTREK-1 was explored in whole cell patch clamp recordings from AZF cells. Inhibition of bTREK-1 by ACTH and forskolin was not affected by the addition of both H-89 and PKI (6-22) amide to the pipette solution at concentrations that completely blocked activation of cAMP-dependent protein kinase (PKA) in these cells. The ACTH derivative, O-nitrophenyl, sulfenyl-adrenocorticotropin (NPS-ACTH), at concentrations that produced little or no activation of PKA, inhibited bTREK-1 by a Ca(2+)-independent mechanism. Northern blot analysis showed that bovine AZF cells robustly express mRNA for Epac2, a guanine nucleotide exchange protein activated by cAMP. The selective Epac activator, 8-pCPT-2'-O-Me-cAMP, applied intracellularly through the patch pipette, inhibited bTREK-1 (IC(50) = 0.63 microM) at concentrations that did not activate PKA. Inhibition by this agent was unaffected by PKA inhibitors, including RpcAMPS, but was eliminated in the absence of hydrolyzable ATP. Culturing AZF cells in the presence of ACTH markedly reduced the expression of Epac2 mRNA. 8-pCPT-2'-O-Me-cAMP failed to inhibit bTREK-1 current in AZF cells that had been treated with ACTH for 3-4 d while inhibition by 8-br-cAMP was not affected. 8-pCPT-2'-O-Me-cAMP failed to inhibit bTREK-1 expressed in HEK293 cells, which express little or no Epac2. These findings demonstrate that, in addition to the well-described PKA-dependent TREK-1 inhibition, ACTH, NPS-ACTH, forskolin, and 8-pCPT-2'-O-Me-cAMP also inhibit these K(+) channels by a PKA-independent signaling pathway. The convergent inhibition of bTREK-1 through parallel PKA- and Epac-dependent mechanisms may provide for failsafe membrane depolarization by ACTH.
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PMID:ACTH inhibits bTREK-1 K+ channels through multiple cAMP-dependent signaling pathways. 1866 35

The hypothalamic-pituitary-adrenal (HPA) axis is activated under various stressors. Corticotropin-releasing factor (CRF) plays a central role in controlling stress response, and regulating the HPA axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN), stimulates adrenocorticotropic hormone (ACTH) production via CRF receptor type 1 (CRF(1) receptor) from the corticotrophs of the anterior pituitary (AP). Cyclic AMP (cAMP)-protein kinase A (PKA) pathway takes a main role in stimulating CRF gene transcription. Forskolin and pituitary adenylate cyclase-activating polypeptide (PACAP) stimulate adenylate cyclase, intracellular cAMP production, and then CRF and arginine vasopressin (AVP) gene expression in hypothalamic 4B cells. Interleukin (IL)-6, produced in the PVN, both directly and indirectly stimulates CRF and AVP gene expression. Estradiol may enhance the activation of CRF gene expression in response to stress. The HPA axis is regulated by a negative feedback mechanism, because glucocorticoids inhibit both CRF production in the hypothalamic PVN and ACTH production in the pituitary. Hypothalamic parvocellular neurons in the PVN are known to express glucocorticoid receptors, and glucocorticoids are able to regulate CRF gene transcription and expression levels directly in the PVN. Glucocorticoids-dependent repression of cAMP-stimulated CRF promoter activity is mainly localized to promoter sequences between -278 and -233 bp. Both negative glucocorticoid regulatory element (nGRE) and serum response element (SRE) are involved in the repression of the CRF gene in the hypothalamic cells.
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PMID:Regulatory mechanisms underlying corticotropin-releasing factor gene expression in the hypothalamus. 1935 56

Growth hormone (GH)-releasing peptides (GHRPs) are synthetic peptides which induce strong GH release in both animals and humans. Among them, GHRP-2 is known to stimulate GH release by acting at both hypothalamic and pituitary sites, but also induces adrenocorticotropic hormone (ACTH) release in healthy subjects. GHRP-2 may stimulate ACTH release directly via GHRP receptor type 1a in ACTH-producing tumors. GHRP-2 increases ACTH secretion in rat in vivo, but not ACTH release from rat primary pituitary cells. In the present study, in order to elucidate the mechanism underlying ACTH secretion by GHRPs, mouse pituitary cells were stimulated by GHRP-2. GHRP receptor mRNA was expressed in the mouse pituitary, and GHRP-2 directly stimulated secretion and synthesis of ACTH in the mouse anterior pituitary cells. GHRP-2 increased intracellular cyclic AMP production. H89, a potent protein kinase A (PKA) inhibitor, and bisindolylmaleimide I, a selective protein kinase C (PKC) inhibitor, inhibited the GHRP-2-induced ACTH release, and that H89, but not bisindolylmaleimide I, inhibited the GHRP-2-induced proopiomelanocortin mRNA levels. Together, the GHRP-2-induced ACTH release was regulated via both PKA and PKC pathways in the mouse pituitary cells, while ACTH was synthesized by GHRP-2 only via the PKA pathway.
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PMID:Growth hormone-releasing peptide-2 stimulates secretion and synthesis of adrenocorticotropic hormone in mouse pituitary. 1968 3


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