Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heat shock protein 90 (hsp90) is a chaperone required for the proper folding and trafficking of many proteins involved in signal transduction. We tested whether hsp90 plays a role as a chaperone for GC-A, the membrane guanylate cyclase that acts as a receptor for atrial natriuretic peptide (ANP). When cultured cells expressing recombinant GC-A were treated with geldanamycin, an inhibitor of hsp90 function, the ANP-stimulated production of cyclic GMP was inhibited. This suggested that hsp90 was required for GC-A processing and/or stability. A physical association between hsp90 and GC-A was demonstrated in coimmunoprecipitation experiments. Treatment with geldanamycin disrupted this association and led to the accumulation of complexes containing GC-A and heat shock protein 70 (hsp70). Protein folding pathways involving hsp70 and hsp90 include several pathway-specific co-chaperones. Complexes between GC-A and hsp90 contained the co-chaperone p50(cdc37), typically found associated with protein kinase.hsp90 heterocomplexes. GC-A immunoprecipitates did not contain detectable amounts of Hop, FKBP51, FKBP52, PP5, or p23, all co-chaperones found in hsp90 complexes with other signaling proteins. The association of hsp90 and p50(cdc37) with GC-A was dependent on the kinase homology domain of this receptor but not on its ANP-binding, transmembrane, or guanylate cyclase domains. The data suggest that GC-A is regulated by hsp90 complexes similar to those involved in the maturation of protein kinases.
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PMID:Regulation of the atrial natriuretic peptide receptor by heat shock protein 90 complexes. 1115 73

Nitric oxide (NO) is a potent bioactive molecule produced in the presence of NO synthase (NOS) enzymes, which mediates numerous physiological functions under constitutive conditions. Sustained overproduction of NO (and NO-reaction products), typically under inductive conditions, can lead to cell cycle arrest and cellular apoptosis. Furthermore, carcinogenesis may result from mutational events following NO-mediated DNA damage and hindrance to DNA repair (e.g., mutation of tumour-suppressor gene p53). In a majority of human and experimental tumours, tumour-derived NO appears to stimulate tumour progression; however, for a minority of tumours, the opposite has been reported. This apparent discrepancy may be explained by differential susceptibility of tumour cells to NO-mediated cytostasis or apoptosis, and the emergence of NO-resistant and NO-dependent clones. NO-resistance may be mediated by p53 inactivation, and upregulation of cyclo-oxygenase-2 and heat shock protein 70 (HSP70). In a murine mammary tumour model, tumour-derived NO promoted tumour growth and metastasis by enhancing invasive, angiogenic, and migratory capacities of tumour cells. Invasion stimulation followed the altered balance of matrix metalloproteases and their inhibitors; migration stimulation followed activation of guanylate cyclase and MAP kinase pathways. Selective NOS inhibitors may have a therapeutic role in certain cancers.
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PMID:Role of nitric oxide in tumour progression with special reference to a murine breast cancer model. 1193 55

Photodynamic therapy (PDT) of cancer is a very promising technique based on the formation of singlet oxygen induced by a sensitizer after irradiation with visible light. The stimulation of tumor growth by nitric oxide (NO) was reported recently, and NO was shown to have a protective effect against PDT-induced tumor death. We investigated a putative direct effect of NO on tumor cell death induced by PDT, using the human lymphoblastoid CCRF-CEM cells and bisulfonated aluminum phthalocyanine (AlPcS2) as a sensitizer. Cells were incubated with AlPcS2 in the presence or absence of NO donors ((Z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, hydroxylamine and S-nitroso-N-acetylpenicillamine) or L-arginine. Under these conditions, in the absence of NO donors or L-arginine the cells died rapidly by apoptosis upon photosensitization. In the presence of NO donors or L-arginine, apoptotic cell death after photosensitization was significantly decreased. Modulation of cell death by NO was not due to S-nitrosylation of caspases and occurred at the level or upstream of caspase-9 processing. The protective effect of NO was reversed by incubating the cells with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylyl cyclase, or with KT5823, an inhibitor of protein kinase G (PKG). Incubation with 8-bromo-cyclic guanosine monophosphate, a membrane permeable cyclic guanosine monophosphate analog, also decreased cell death induced by PDT. Although the protective effect of NO against apoptotic cell death in several models has been attributed to an increase in the expression of heme oxygenase-1, heat shock protein 70 or Bcl-2, this was not the case under our experimental conditions. These results show that NO decreases the extent of apoptotic cell death after PDT treatment through a PKG-dependent mechanism, upstream or at the level of caspase activation.
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PMID:Nitric oxide modulates tumor cell death induced by photodynamic therapy through a cGMP-dependent mechanism. 1240 51

In brain, a brief ischemic episode induces protection against a subsequent severe ischemic insult. This phenomenon is known as preconditioning-induced neural ischemic tolerance. An understanding of the molecular mechanisms leading to preconditioning helps in identifying potential therapeutic targets for preventing the post-stroke brain damage. The present study conducted the genomic and proteomic analysis of adult rat brain as a function of time following preconditioning induced by a 10-min transient middle cerebral artery (MCA) occlusion. GeneChip analysis showed induction of 40 putative neuroprotective transcripts between 3 to 72 h after preconditioning. These included heat-shock proteins, heme oxygenases, metallothioneins, signal transduction mediators, transcription factors, ion channels and apoptosis/plasticity-related transcripts. Real-time PCR confirmed the GeneChip data for the transcripts up-regulated after preconditioning. Two-dimensional gel electrophoresis combined with MALDI-TOF analysis showed increased expression of HSP70, HSP27, HSP90, guanylyl cyclase, muskelin, platelet activating factor receptor and beta-actin at 24 h after preconditioning. HSP70 protein induction after preconditioning was localized in the cortical pyramidal neurons. The infarct volume induced by focal ischemia (1-h MCA occlusion) was significantly smaller (by 38 +/- 7%, p < 0.05) in rats subjected to preconditioning 3 days before the insult. Preconditioning also prevented several gene expression changes induced by focal ischemia.
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PMID:Putative endogenous mediators of preconditioning-induced ischemic tolerance in rat brain identified by genomic and proteomic analysis. 1503 Mar 91