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)

Addition of cGMP to cytosol of human endometrium or to cells of the endometrial cancer line HEC-1 produced severalfold increases in specific estrogen binding (EB) levels. This effect was maximal with 1 microM cGMP in the presence of 0.1 mM isobutylmethylxanthine (a phosphodiesterase inhibitor) during incubations with [3H]estradiol. In contrast, cAMP decreased EB levels under similar conditions. The effects of cyclic nucleotides on EB levels were complete in less than 15 min in the presence of Mg2+, Mn2+, or Ca2+. The EB sites generated by the addition of cGMP during labeling of cytosol with 10 nM [3H]estradiol were found to sediment in the 8S and 4S regions of low-salt glycerol gradients. No changes in EB levels were observed when cyclic nucleotides were added to cytosol depleted of ATP by preincubation at 4 degrees C for 3 hr, but responsiveness was restored by addition of exogenous ATP. The ATP requirement and the pattern of dependence of cyclic nucleotide actions on divalent cation concentrations suggest that cGMP and cAMP effects may be mediated by kinases and may involve phosphorylations. Another possibility is that the cyclic nucleotides interact allosterically with the binder in the presence of ATP. Addition of sodium molybdate, ATP, and GTP to homogenates of endometrial tissue or HEC-1 cells produces increases in EB levels similar to those obtained by the addition of cGMP. However, these compounds are much less active when added to cytoplasm or cytosol. On the basis of these and other observations, it is hypothesized that molybdate, ATP, and GTP affect EB levels primarily by increasing cGMP concentrations through processes involving a plasma membrane-bound guanylate cyclase.
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PMID:Rapid changes in specific estrogen binding elicited by cGMP or cAMP in cytosol from human endometrial cells. 630 87

Recent experimental results from our laboratories revealed the following facts: Addition of GMP to homogenates or cytosol prepared from endometrial tissue or cultured endometrial adenocarcinoma cells during the assay for specific estrogen binders markedly increases specific binding levels. The effect is completed in about 15 min at 4 C (Fleming et al, 1983). Cyclic AMP has the opposite effect and in many cases lowers the number of binding sites to undetectable levels. ATP, a nucleotide that stimulates a particulate form of guanylate cyclase, Na2MoO4, a compound that can elevate cGMP levels (Fleming and Blumenthal, unpublished) and GTP, a metabolic precursor of cGMP, increase specific estradiol binding in the presence of plasma membranes and soluble factors. Cyclic AMP reduces the levels of estrogen binding when added to cell homogenates or to cytosol and counteracts the effects of cGMP, MoO4, ATP and GTP. ATP is required for the expression of cGMP and cAMP effects on estradiol binding. It is therefore likely that phosphorylations are involved in the generation and inactivation of estrogen binding sites. Divalent cation requirements for these effects also suggest participation of protein kinases in these processes. The reported effects of nucleotides and molybdate have been observed in specimens of histologically normal endometrium, in specimens of endometrial carcinoma, in two endometrial adenocarcinoma cell lines, HEC-1 and HEC-50 (Suzuki et al, 1980), and in two breast cancer cell lines, CG-5, a variant of MCF-7 obtained in Iacobelli's laboratory (Natoli et al, 1983), and in T47D) (Fleming et al, in press) Rapid changes in the levels of estrogen binding capacity observed in endometrial cells in culture can be associated with changes in cGMP/cAMP ratios shown, to vary during the cell cycle. Although it has not yet been demonstrated that cGMP-induced increases in specific estrogen binding can enhance responses to available estrogens, such possibility is of potential importance. Reduction of estrogen receptor levels in patients with cancers of estrogen sensitive tissues may inhibit tumor growth promoted by endogenous estrogen. Cho-Chung et al have recently reported that cholera toxin causes a reduction in estrogen receptor levels and arrests hormone dependent growth of DMBA-induced mammary carcinoma in rats (Cho-Chung et al, 1983). They postulated that the effect of cholera toxin is mediated by a cAMP effect on the estrogen receptor, an hypothesis supported by the observation that only tumors containing receptor responded to treatment. Conversely, cGMP-induced increases in specific estrogen binders may be useful in promoting a response of tumors to estr
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PMID:Regulation of estrogen receptor levels in endometrial cancer cells. 670 55