Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunoregulatory C-C chemokine, macrophage inflammatory protein-1 alpha (MIP-1 alpha) has suppressive activity on proliferation of stem cells and early subsets of myeloid progenitor cells. A receptor for C-C chemokines that binds MIP-1 alpha has been characterized, cloned, and shown to be related structurally to neuropeptide receptors that couple through G-proteins to phospholipase-C and adenyl cyclase. Yet, very little information on the intracellular mechanisms of action of MIP-1 alpha is available. We show here that the human factor-dependent cell line M07e is responsive to the cell cycle-suppressive effects of MIP-1 alpha, has specific membrane-binding sites for MIP-1 alpha, and that treatment of these cells with this chemokine increases the phosphatidylcholine (PC) and phosphocholine turnover rates in cells that are synergistically stimulated by the combination of granulocyte-macrophage colony-stimulating factor and steel factor but not these factors acting singly. Additional, MIP-1 alpha treatment induces a dose- and time-dependent increase in intracellular cAMP levels in M07e cells. Both exogenous PC and dibutyryl cAMP were found to suppress the proliferation of M07e colony-forming cells to a level similar to that of MIP-1 alpha, further implicating cAMP and PC metabolism in MIP-1 alpha-induced M07e suppression. RANTES, a related chemokine, with weak or incomplete binding to the cloned MIP-1 alpha receptor, did not suppress M07e colony-forming cells, nor did it increase intracellular cAMP levels, but it did enhance growth factor-induced PC turnover, further supporting the involvement of cAMP in MIP-1 alpha suppression while demonstrating that increased PC turnover alone is not sufficient for suppression. These findings support the idea that the human MIP-1 alpha receptor is coupled to phospholipid and cAMP metabolism in a manner similar to other 7-transmembrane, G-protein-linked receptors and suggest that a phosphatidylcholine hydrolytic cycle and an associated increase in cAMP are part of the mechanisms of action of MIP-1 alpha.
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PMID:Macrophage inflammatory protein-1 alpha enhances growth factor-stimulated phosphatidylcholine metabolism and increases cAMP levels in the human growth factor-dependent cell line M07e, events associated with growth suppression. 753 66

A GHRH-like mRNA and peptide (t-GHRH) have been detected in rat and human testis. In rat, t-GHRH mRNA is localized to developing spermatogenic cells. We predicted that the most likely target cell of t-GHRH action would be the Sertoli cell. To test this prediction, we evaluated GHRH action on Sertoli cell function. Rat GHRH at a concentration of 10 nM or 100 nM stimulated cAMP production 2-fold over control levels after a 30 min incubation. This stimulation was obliterated by preincubation with a 10-fold excess of the GHRH antagonist (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2. The effect of treatment with [His1,Nle27]GHRH(1-32)-NH2, a GHRH analog, on Sertoli cell mRNAs was also assessed. Treatment with the analog significantly increased levels of c-fos and steel factor (the product of the Steel gene, also termed SCF) mRNAs above controls, but had no effect on sulfated glycoprotein-2 mRNA. We conclude that GHRH acts via adenylate cyclase to modulate specific Sertoli cell products, possibly as part of a network of local interacting factors controlling Sertoli and germ cell function.
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PMID:A new target for growth hormone releasing-hormone action in rat: the Sertoli cell. 768 61

Chromatophores are specialized integumental stellate cells that synthesize and store pigments. Pigment granules are translocated within chromatophores of poikilothermic vertebrates and crustaceans in response to photic, thermal and/or neurohormonal stimuli, allowing the animal to rapidly change color for thermoregulation, adaptation to light and background, and social behavior display. Birds and mammals do not show color changes, but may present slow long-term responses, such as melanocyte proliferation, melanin synthesis and melanin granule translocation into feathers, hair and surrounding keratinocytes. Pigment translocation in lower vertebrates as well as pigment production in all vertebrates are modulated by a variety of hormones and neurotransmitters acting on transmembrane receptors located on the cell surface. Alpha-melanocyte-stimulating hormone (alpha-MSH), melanin-concentrating hormone (MCHA), melatonin and catecholamines are the most important pigment cell agonist in vertebrates. The major signalling pathway leading to pigment dispersion and melanin synthesis appears to be involve stimulation of adenylate cyclase followed by an increase in the cAMP level and activation of cAMP-dependent protein kinases (PKAs). Another melanogenesis-related intracellular pathway involves the activation of protein kinase C (PKC) by diacylglycerol, and the increase in cytosolic Ca2+ by inositol triphosphate. Growth factors such as basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF) and mast cell growth factor (MGF or KIT ligand), and UV radiation modulate the melanogenic and mitogenic processes in vertebrate melanocytes as well.
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PMID:Cellular signalling in vertebrate pigment cells. 922 39

Kit ligand (Kitl) is an important paracrine factor involved in the activation of primordial follicles from the quiescent pool and in the maintenance of meiotic arrest before germinal vesicle breakdown (GVBD). It has been reported that follicle-stimulating hormone (FSH) stimulates but luteinizing hormone (LH) suppresses the expression of Kitl in the granulosa cells in mammals. Considering that both gonadotropins signal in the follicle cells mainly by activating cyclic adenosine 3', 5'-monophosphate (cAMP) pathway, we are intrigued by how cAMP differentially regulates Kitl expression. In the present study, we demonstrated that both human chorionic gonadotropin (hCG) and pituitary adenylate cyclase activating polypeptide (PACAP) inhibited insulin-like growth factor I (IGF-I)-induced Akt phosphorylation and kitlga expression in the zebrafish follicle cells. Further experiments showed that cAMP was involved in regulating the expression of kitlga. However, two cAMP-activated effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), had converse effects. PKA promoted whereas Epac inhibited the expression of kitlga, as demonstrated by the respective activators. Interestingly, cAMP also appeared to exert differential effects on kitlga expression at different stages of follicle development during folliculogenesis, significantly stimulating kitlga expression at the early growth stage but suppressing it at the full-grown stage before final oocyte maturation, implying a potential mechanism for differential effects of the same pathway at different stages. The inhibitory effect of forskolin (activator of adenylate cyclase) and H89 (inhibitor of PKA) on IGF-I-induced expression of kitlga suggested cross-talk between the cAMP and IGF-I-activated PI3K-Akt pathways. This study, together with our previous findings on IGF-I regulation of kitlga expression, provides important clues to the underlying mechanism that regulates Kit ligand expression during folliculogenesis in the ovary.
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PMID:Differential regulation of kit ligand A (kitlga) expression in the zebrafish ovarian follicle cells--evidence for the existence of a cyclic adenosine 3', 5' monophosphate-mediated binary regulatory system during folliculogenesis. 2554 47