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)

The growth of C6 glioma and L1210 leukemic cells has been stimulated in serum-free medium by the addition or iron or transferrin. The growth promoting action of transferrin was lost when iron was chelated in the culture medium using desferrioxamine. L1210 cells can be grown continuously in serum-free medium supplemented with transferrin or FeCl3 only. In this latter case, it has been shown that L1210 cells secrete into the medium some factor which facilitates iron uptake. The growth of L1210 cells in their exponential phase was blocked by desferrioxamine at the G1-S interface of the cell cycle. The action of transferrin on cell growth was also inhibited by propyl gallate - a known antioxidant which prevents lipid peroxidation. The action of iron was more potent than hemin in reversing the influence of propyl gallate on L1210 cell growth. Iron was found to activate purified guanylate cyclase in the presence of unsaturated fatty acids. This suggests that cyclic GMP synthesis could be involved in the promotion of transformed cell growth by iron.
 ...
PMID:Growth promotion of transformed cells by iron in serum-free culture. 285 72

In the testis the mesenchymally derived peritubular cells produce a paracrine factor, PModS, that mediates mesenchymal-epithelial interactions and modulates Sertoli cell functions essential for the process of spermatogenesis. PModS has a more dramatic effect on Sertoli cell differentiated functions in vitro than any regulatory agent previously shown to influence the cells, including FSH. The current study initiates an investigation of the pharmacology of PModS through an analysis of several common signal transduction pathways. PModS was found to stimulate cGMP levels in Sertoli cells and maintain elevated levels for up to 5 days in culture. PModS had no influence on cAMP levels. In contrast, FSH stimulated cAMP, but had no influence on cGMP levels. For comparison, an agent known to influence cGMP levels, atrial naturetic factor (ANF), was used to treat Sertoli cells. ANF caused a dramatic increase in Sertoli cell cGMP levels within minutes of treatment, but did not maintain elevated cGMP levels after a 72-h treatment. Although ANF increased guanylate cyclase in whole Sertoli cell homogenates and particulate fractions, PModS did not directly influence guanylate cyclase activity. As previously shown, PModS stimulates transferrin expression as a marker of Sertoli cell differentiated function. Agents that elevate cellular cGMP, including ANF, sodium nitroprusside, and 8-bromo-cGMP, did not influence Sertoli cell transferrin expression. In addition, these agents did not influence the actions of PModS or FSH. Therefore, cGMP does not appear to directly mediate the actions of PModS. As an alternative signal transduction pathway, calcium mobilization and inositol phosphate (IP) metabolism were examined. PModS did not alter calcium uptake or intracellular calcium mobilization. PModS also did not influence the levels of inositol mono-, bis-, or trisphosphates, whereas calf serum did stimulate levels of all three IP metabolites in Sertoli cells. Therefore, PModS does not appear to act through a mobilization of calcium or increased metabolism of IP. A final signal transduction pathway involving phosphorylation was also examined. PModS treatment was found to increase tyrosine phosphorylation of specific proteins in a crude Sertoli cell cytosol preparation. Genistein is an inhibitor of tyrosine kinases and was found to reduce PModS actions at a 3.7-microM concentration of genistein and inhibit PModS actions at a 37-microM concentration of genistein. Therefore, PModS may act through a tyrosine phosphorylation event that remains to be elucidated. Combined observations indicate that PModS does not use cyclic nucleotides, calcium mobilization, or IP metabolism as a signal transduction pathway.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Regulation of Sertoli cell differentiation by the testicular paracrine factor PModS: analysis of common signal transduction pathways. 790 30

Heme oxygenase (HO) proteins are members of the HSP30 family and consist of 2 isozymes identified to date, termed HO-1 and HO-2. Separate genes encode the isozymes and protein products which are immunochemically distinct, share less than 50% similarity at the amino acid sequence level. Each form, however, shows greater than 90% similarity among species, including human and the rat (reviewed in ref.). Furthermore, these isozymes function in a well-defined role to carry out oxidation of the heme molecule (Fe-protoporphyrin IX) in concert with NADPH-cytochrome P450 reductase. The oxidation of heme is isomer specific and results in the formation of bile pigments, carbon monoxide, and iron. The heme molecule constitutes the prosthetic moiety of hemoproteins, such as hemoglobin, myoglobin, catalase, soluble guanylate cyclase, cytochrome b5, cytochromes P450 and NO synthase. HO-1 also known as heat shock protein (HSP) 32 is encoded by a gene which is exquisitely stress-responsive and a host of stimuli that mediate oxidative stress cause induction of the protein both in vivo and in vitro. The HO-2 form shows a unique pattern of regulation from that of HO-1. HO-2 is a constitutive protein and its expression is not affected by the inducers of HO-1 tested to date; rather, the only known regulator of HO-2 yet identified is adrenal glucocorticoids. The two isozymes display vast differences in tissue distribution and under normal conditions HO-1 is present in the whole brain at the limit of immunodetection and is discreetly localized in select neuronal populations. HO-1 protein (approximately 32 kDa) and its approximately 1.8 kb transcript are increased, however, in response to stressful stimuli primarily in non-neuronal cell populations. The heme oxygenase system serves in both a catabolic and anabolic capacity in the cell. In the former capacity, it down-regulates cellular heme and hemoprotein levels. And, as such it inactivates the most effective catalyst for formation of free radicals, the heme molecule. In its anabolic role, as noted above, heme oxygenase produces bile pigments, carbon monoxide, and iron, all of which are biologically active: bile pigments function as antioxidants; the carbon monoxide generated by HO activity has been correlated with the generation of cGMP; and iron regulates expression of various genes, including that of HO-1 itself, as well as transferrin receptors, ferritin, and NO synthase. We used rabbit anti-rat HO-2 polyclonal antibody and HO-2 cDNA to localize HO-2 immunoreactive protein and the 1.3- and 1.9 kb homologous transcripts, respectively, in rodent brain as visualized by histochemical staining procedures. These protocols provide the first detailed description of methodologies successfully used to define the pattern of HO-2 expression at the transcriptional and translational levels in the adult rat brain and glucocorticoid-treated newborn rats. The procedures described herein have the virtue of being non-radioactive, as well as applicability to the systemic organs, such as the cardiovascular system and the male reproductive organs. Visualization of cellular HO-2 expression aids in assessment of potential sites of carbon monoxide, iron, and bilirubin production within the nervous system.
 ...
PMID:Histochemical localization of heme oxygenase-2 protein and mRNA expression in rat brain. 938 81

Heme is a complex of iron with protoporphyrin IX that is essential for the function of all aerobic cells. Heme serves as the prosthetic group of numerous hemoproteins (eg, hemoglobin, myoglobin, cytochromes, guanylate cyclase, and nitric oxide synthase) and plays an important role in controlling protein synthesis and cell differentiation. Cellular heme levels are tightly controlled; this is achieved by a fine balance between heme biosynthesis and catabolism by the enzyme heme oxygenase. On a per-cell basis, the rate of heme synthesis in the developing erythroid cells is at least 1 order of magnitude higher than in the liver, which is in turn the second most active heme producer in the organism. Differences in iron metabolism and in genes for 5-aminolevulinic acid synthase (ALA-S, the first enzyme in heme biosynthesis) are responsible for the differences in regulation and rates of heme synthesis in erythroid and nonerythroid cells. There are 2 different genes for ALA-S, one of which is expressed ubiquitously (ALA-S1), whereas the expression of the other (ALA-S2) is specific to erythroid cells. Because the 5'-untranslated region of the erythroid-specific ALA-S2 mRNA contains the iron-responsive element, a cis-acting sequence responsible for translational induction of erythroid ALA-S2 by iron, the availability of iron controls protoporphyrin IX levels in hemoglobin-synthesizing cells. In nonerythroid cells, the rate-limiting step of heme production is catalyzed by ALA-S1, whose synthesis is feedback-inhibited by heme. On the other hand, in erythroid cells, heme does not inhibit either the activity or the synthesis of ALA-S but does inhibit cellular iron acquisition from transferrin without affecting its utilization for heme synthesis. This negative feedback is likely to explain the mechanism by which the availability of transferrin iron limits heme synthesis rate. Moreover, in erythroid cells heme seems to enhance globin gene transcription, is essential for globin translation, and supplies the prosthetic group for hemoglobin assembly. Heme may also be involved in the expression of other erythroid-specific proteins. Furthermore, heme seems to play a role in regulating either transcription, translation, processing, assembly, or stability of hemoproteins in nonerythroid cells. Heme oxygenase, which catalyzes heme degradation, seems to be an important enzymatic antioxidant system, probably by providing biliverdin, which is an antioxidant agent.
 ...
PMID:Cell biology of heme. 1052 52