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PubMed1993

Isolation and characterization of a novel cDNA which identifies both neural-specific and ubiquitously expressed GS alpha mRNAs.

Heterotrimeric G proteins consisting of alpha, beta, and gamma subunits couple sensory, hormone, and neurotransmitter receptors to intracellular and transmembrane effectors. Several splicing variants of the GS (the G protein that stimulates adenylyl cyclase) alpha subunit (GS alpha) have been described. Some of these couple receptors to stimulation of adenylyl cyclase and Ca2+ channels, whereas others encode truncated proteins whose functions are not currently defined. We describe a 1321N1 human astrocytoma cDNA clone for a novel GS alpha isoform isolated from astrocytoma cells (G(astro)) that is identical to GS alpha-1 with the exception of a novel 5' sequence extending into the previously described exon 1 of GS alpha, a single base change, and an alternative polyadenylation site. Analysis by northern blotting and reverse transcription/PCR confirms the presence of an mRNA corresponding to this cDNA in astrocytoma cells. Additional northern analysis indicates that G(astro) recognizes two novel GS alpha mRNAs in the rat: a 2.0-kb mRNA expressed only in neural and neuroendocrine tissues and a 1.8-kb mRNA that is ubiquitously expressed. Functional analysis of G(astro) is complicated by the apparent insertion of alphoid satellite DNA into the transcription unit. The resulting cDNA encodes a truncated protein that may be translated from the methionine in exon 2 as previously described.

Amino Acid Sequence↗

PubMed1990

Anaerobic Oxidation of Toluene, Phenol, and p-Cresol by the Dissimilatory Iron-Reducing Organism, GS-15.

The dissimilatory Fe(III) reducer, GS-15, is the first microorganism known to couple the oxidation of aromatic compounds to the reduction of Fe(III) and the first example of a pure culture of any kind known to anaerobically oxidize an aromatic hydrocarbon, toluene. In this study, the metabolism of toluene, phenol, and p-cresol by GS-15 was investigated in more detail. GS-15 grew in an anaerobic medium with toluene as the sole electron donor and Fe(III) oxide as the electron acceptor. Growth coincided with Fe(III) reduction. [ring-C]toluene was oxidized to CO(2), and the stoichiometry of CO(2) production and Fe(III) reduction indicated that GS-15 completely oxidized toluene to carbon dioxide with Fe(III) as the electron acceptor. Magnetite was the primary iron end product during toluene oxidation. Phenol and p-cresol were also completely oxidized to carbon dioxide with Fe(III) as the sole electron acceptor, and GS-15 could obtain energy to support growth by oxidizing either of these compounds as the sole electron donor. p-Hydroxybenzoate was a transitory extracellular intermediate of phenol and p-cresol metabolism but not of toluene metabolism. GS-15 oxidized potential aromatic intermediates in the oxidation of toluene (benzylalcohol and benzaldehyde) and p-cresol (p-hydroxybenzylalcohol and p-hydroxybenzaldehyde). The metabolism described here provides a model for how aromatic hydrocarbons and phenols may be oxidized with the reduction of Fe(III) in contaminated aquifers and petroleum-containing sediments.

Journal Article↗

PubMed1995

The small envelope glycoprotein (GS) of equine arteritis virus folds into three distinct monomers and a disulfide-linked dimer.

The small membrane glycoprotein (GS) of equine arteritis virus (EAV) is a minor virion component but is abundantly expressed in EAV-infected cells. In this study, we have analyzed its membrane topology, folding, oligomerization, and intracellular transport. We show that GS is a class I integral membrane protein with one functional N-glycosylation site. Gel electrophoresis under nonreducing conditions revealed that GS occurs in EAV-infected cells in four monomeric conformations and as disulfide-linked homodimers. The slowest-migrating monomeric form corresponded to the fully reduced GS protein; the three faster-migrating monomeric species are probably generated by the formation of alternative intrachain disulfide bonds between the three luminal cysteines in the molecule. The GS monomers were selectively retained in the endoplasmic reticulum, as judged by their permanent susceptibility to endoglycosidase H, whereas the GS dimers were specifically incorporated into virus particles and became endoglycosidase H resistant and sialylated during passage through the Golgi apparatus.

Amino Acid Sequence↗

PubMed1990

Membrane-delimited stimulation of heart cell calcium current by beta-adrenergic signal-transducing Gs protein.

A severalfold increase in calcium current (ICa) is a signal feature of the maximal beta-adrenergic response of the heart. It is generally ascribed to enhanced adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphorylation of calcium (Ca) channels after beta-receptor activation of the guanosine nucleotide-binding (G) protein Gs, and Gs activation of the adenylyl cyclase cascade. We blocked phosphorylation pathways in guinea pig cardiomyocytes to unmask other possible ICa-stimulatory modes. In blocked cells, ICa increased by approximately 50% during 1) beta-receptor activation of Gs, 2) intracellular activation of Gs, and 3) intracellular application of preactivated Gs, We conclude that fast, membrane-delimited Gs modulation participates in the physiological regulation of cardiac ICa.

Animals↗

PubMed1998

The third intracellular loop of the rat gonadotropin-releasing hormone receptor couples the receptor to Gs- and G(q/11)-mediated signal transduction pathways: evidence from loop fragment transfection in GGH3 cells.

The GnRH receptor (GnRH-R) belongs to the rhodopsin/beta-adrenergic family of G protein-coupled receptors. The intracellular domains of these receptors, particularly the regions closest to the plasma membrane in intracellular loops 2 (2i) and 3 (3i) as well as some regions located in the membrane-proximal end of the COOH-terminus, are frequently important sites for G protein coupling and specificity determination. Although studies in mouse and human GnRH-R have identified loop 2i as a critical determinant for coupling the receptor to the G(q/11)-mediated signal transduction pathway, given the functional similarity among the members of this particular G protein-coupled receptor subfamily and the fact that the GnRH-R lacks the typical intracellular COOH-terminal domain of its superfamily (a potential site for G protein coupling), we investigated the possibility that loop 3i of this receptor also participates in GnRH-R coupling to G proteins. GGH(3)1' cells, a pituitary-derived cell line that expresses a functional rat GnRH-R coupled to both Gs and G(q/11) proteins, were transiently transfected with a plasmid DNA containing a complementary DNA (cDNA) coding for the entire loop 3i of the GnRH-R as well as with other expression plasmids containing cDNAs encoding loop 3i of other Gs-, G(i/o)-, or G(q/11)-coupled receptors. The effects of coexpression of these loops with the wild-type GnRH-R on inositol phosphate (IP) production, cAMP accumulation, and PRL release were then examined. Transfection of GGH(3)1' cells with the cDNA for loop 3i of the rat GnRH-R (efficiency, 35-45%) maximally inhibited buserelin-stimulated IP turnover by 20% as well as cAMP accumulation and PRL secretion by 30%. This attenuation in cellular responses to a GnRH agonist was statistically significant (P < 0.05) compared with the responses exhibited by GGH(3)1' cells transfected with a control plasmid and stimulated with the same GnRH agonist. Transfection of minigenes coding for loop 3i of the M1Ach-muscarinic and the alpha1B-adrenergic (G(q/11)-coupled) receptors resulted in 25-55% inhibition of maximal GnRH-evoked IP turnover. Paradoxically, loop 3i from the M1Ach-muscarinic receptor also maximally inhibited GnRH agonist-stimulated cAMP accumulation and PRL release by 40% (both effects mediated through activation of the Gs protein). Transfection of loop 3i from the D1A -dopamine receptor (coupled to the Gs protein) produced a selective attenuation (40%) in Gs-mediated cellular responses. In contrast, receptor/G protein coupling appeared unaffected by expression of loop 3i domains derived from two receptors coupled to G(i/o) proteins (M2Ach-muscarinic and alpha2A-adrenergic receptors). These data indicate that the third intracellular loop of the rat GnRH-R is involved in receptor G(q/11) protein coupling and/or selectivity, and in the GGH(3)1' cell line, this loop is also involved in signal transduction mediated through the Gs protein pathway.

Amino Acid Sequence↗

PubMed1994

Growth hormone-prolactin-thyrotropin-secreting pituitary adenoma in atypical McCune-Albright syndrome with functionally normal Gs alpha protein.

The McCune-Albright syndrome (MAS) comprises a triad of physical signs: localized bone lesions termed polyostotic fibrous dysplasia, café-au-lait pigmentation of the skin, and autonomous hyperfunction of multiple endocrine systems, including overproduction of GH and T4. A somatic activating point mutation in the gene for the alpha-subunit of the G-protein (Gs alpha) in the affected tissue has been claimed to be the underlying defect. A 29-yr-old patient with MAS, showing polyostotic fibrous dysplasia associated with acromegalic features, underwent endocrinological studies, including oral glucose tolerance test and pituitary stimulation test, and magnetic resonance imaging, revealing elevated plasma concentrations of GH, PRL, and secondary hyperthyroidism due to pituitary macroadenoma infiltrating the sphenoid cavity and extending to the suprasellar space. Subsequently, reduction of tumor mass by a transsphenoidal and a subsequent subfrontal operation led to only marginal amelioration of the excessive hormone production. Postsurgery octreotide and bromocriptine therapy induced near-normalization of hormone concentrations. Immunohistochemistry of tumor tissue confirmed the plurihormonal character, but DNA sequence analysis did not detect any of the two known activating mutations in the Gs alpha gene. Furthermore, biochemical tests revealed normal Gs alpha function, ruling out other mutations that lead to constitutive Gs alpha activation. Our study documents that MAS is a heterogeneous disease. Some, but clearly not all, patients have oncogenic mutations of the gene coding for Gs alpha. Any gene acting down-stream of Gs can theoretically be predicted to result in the same phenotype. In addition, hyperthyroidism of MAS may be secondary to a TSH-producing pituitary macroadenoma.

Adenoma↗

PubMedDate not supplied

Cellular heterogeneity of rat vascular endothelium as detected by HPA and GS I lectin-gold probes.

BACKGROUND: In order to extend previous observations on the heterogeneity in labeling of rat vascular endothelium by the lectins GS I and LEA [1,2], we have conducted a survey of several organs with a lectin panel with greater variety of carbohydrate specificity. MATERIAL AND METHODS: Submandibular gland, duodenum, distal colon, liver, kidney, heart, skeletal muscle, adrenal gland, ovary, cerebral and cerebellar cortex of a rat have been examined by light and electron microscopy using lectin-gold probes on Lowicryl K4M embedded tissue. RESULTS: Five lectins (LCA, con A, LEA, RCA, WGA) labeled vascular endothelial cells in the connective tissue of all the organs studied, while PNA, EEA, TPA, LABA, UEA I expressed no detectable affinity towards endothelial cells. HPA and GS I reacted with most endothelial cells, except those in the kidney glomeruli, liver sinusoids and zona fasciculata of adrenal gland. In cerebral and cerebellar cortex GS I reacted witn pericytes of large vessels, but not with endothelial cells of the capillary bed. SDS-PAGE extracts of heart, skeletal muscle and cerebral cortex reveal that differences in GS I labeling depend, at least in part, on 40 and 200 kD glycoproteins, present in heart and skeletal muscle, but not cerebral cortex. CONCLUSIONS: Data indicate, that GS I, widely used for selective histochemical labeling of rat endothelial cells is not uniform endothelial marker in all organs. More precise investigation of these lectin reactive determinants in rat vascular endothelium, including developmental changes, isolation and enzyme-FACE sequencing of their carbohydrate moieties, generation of antibodies and their possible organ specific binding affinities could give new insight into the physiological role of GS I and HPA binding glycoproteins in rat endothelium.

Animals↗

PubMed2005

Construction of an effective m1 GS ribozyme targeting HCMV UL97 mRNA segment in vitro.

A sequence-specific M1GS ribozyme (M1-T3) was constructed by covalently linking an oligonucleotide (guide sequence,GS) to the 3' terminus of M1 RNA ,the catalytic subunit of RNase P from Escherichia coli. The engineered ribozyme is targeted to the mRNA sequence encoding a protein kinase (UL97) of HCMV and could effectively cleave the mRNA segment in vitro. Further studies about the significance of some structural elements in the M1 GS (e.g. the 3' CCA tail sequence and a bridge sequence between the 3' terminus of M1 RNA and the 5' terminus of the GS) were carried out. The results showed that the bridge sequence of 88 nucleotides in a mutated M1 GS (i.e. M1-T3*) dramatically increased the cleavage activity to the substrate in vitro. Moreover, the 3'CCA tail sequence was confirmed to be a necessary element for the cleavage activity of M1 GS ribozyme. These data we got in the study will help in understanding the interaction between the M1 GS RNA and its substrate,and will markedly facilitate the research of a general gene targeting agent for anti-HCMV applications.

5' Untranslated Regions↗

PubMed1992

The G226A mutant of Gs alpha highlights the requirement for dissociation of G protein subunits.

Adenylylcyclase cannot be activated by hormones or guanine nucleotide analogs in membranes from cells that express the G226A mutant form Gs alpha instead of the wild-type protein. The mutant Gs alpha protein appears incapable of undergoing the conformational change necessary for guanine nucleotide-induced dissociation of the G protein alpha subunit from the beta gamma subunit complex (Miller, R.T., Masters, S.B., Sullivan, K.A., Beiderman, B., and Bourne, H.R. (1988) Nature 334, 712-715). G226A Gs alpha was synthesized in Escherichia coli, purified, and characterized. Examination of the kinetics of dissociation of guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) suggests that G226A Gs alpha is incapable of assuming the conformation necessary for high affinity binding of Mg2+ to the alpha subunit-GTP gamma S complex. Associated changes include the failure of Mg2+ and GTP gamma S to confer resistance to tryptic proteolysis upon the protein, to enhance intrinsic tryptophan fluorescence, or to cause dissociation of alpha from beta gamma. However, the GTPase activity of the mutant protein is near normal (at high Mg2+ concentrations), and the protein is capable of activating adenylylcyclase. A similar defect is present in G49V Gs alpha. Failure of G protein subunit dissociation appears to be the explanation for the phenotypic properties of cells that express G226A Gs alpha, and this mutation thus highlights the crucial nature of this reaction as a component of G protein action.

Adenylyl Cyclases↗

PubMed1989

[Release of adenylate cyclase stimulating, GTP-binding protein, Gs from human erythrocyte membranes under the effect of fluoride-ion and guanine nucleotides].

Human erythrocyte membranes were incubated in the presence of sodium fluoride or guanylylimidodiphosphate (GppNHp), a nonhydrolysable GTP analog. After centrifugation at 100000 g the activity of the adenylate cyclase-stimulating GTP-binding protein, Gs, was detected in the supernatant fraction. The release of the Gs activity from the membranes closely resembles Gs activation by GppNHp. The Gs activity release from the GppNHp-induced membranes is characterized by a lag period. The nucleotide concentration causing a half-maximal solubilization is about 9.10(-7) M. Approximately 50% of the Gs activity released from sodium fluoride-treated human erythrocyte membranes was associated with the cytoskeletal fraction extracted by a low ionic strength solution. The data obtained suggest that Gs exists in the membrane at lease in two compartmentalized states and is solubilized from both states during its activation.

Adenylyl Cyclases↗

PubMed1988

Estrogen reduces beta-adrenoceptor-mediated cAMP production and the concentration of the guanyl nucleotide-regulatory protein, Gs, in rabbit myometrium.

The uterine contractile response to adrenergic agonists or sympathetic stimulation is influenced dramatically by the hormonal milieu. Rabbit uterine contraction is mediated by alpha 1-adrenoceptors, whereas relaxation in response to the same stimulus is mediated by beta 2-adrenoceptors. Whether uterine contractility is increased or decreased by adrenergic stimulation is determined by the gonadal steroids estrogen and progesterone: uterine contraction prevails in the estrogen-dominant or the ovariectomized animal, but in the progesterone-dominant rabbit, uterine relaxation is observed. In previous studies, we have demonstrated that changes in the concentration or agonist affinity of these adrenoceptors cannot account for the changes in contractile response. In the present studies, we tested whether sex steroids might alter beta-adrenergic response by acting on events distal to receptor occupancy, and whether this could explain the conversion of contractile response. We found that myometrial cAMP generation is potently stimulated by beta-agonists in progesterone-treated and also in ovariectomized animals, but this stimulation is absent after estrogen treatment. Similar, but smaller, changes were observed for cAMP generation in response to prostaglandin E2 and forskolin. Stimulation of adenylate cyclase in uterine particulates by agents which act on the guanyl nucleotide-sensitive stimulatory transducer, Gs, is unchanged after estrogen treatment. However, specific labeling of Gs catalyzed by cholera toxin is reduced in membrane particulates from estrogen-treated animals. Recombination of extracts of uterine membranes from the differently treated animals also suggested qualitative differences in Gs. We conclude that at least one component of the adenylate cyclase cascade beyond the beta-adrenoceptor, i.e., Gs, is a target for ovarian steroids; estrogen reduces Gs labeling and beta-adrenoceptor-mediated cAMP production. However, uterine Gs labeling and cAMP production are similar in ovariectomized and in progesterone-treated rabbits. Since these uteri exhibit different contractile responses, the observed changes are not sufficient to explain sex steroid-mediated conversion of myometrial contractile response.

Adenosine Diphosphate Ribose↗

PubMed1985

Forskolin potentiation of cholera toxin-stimulated cyclic AMP accumulation in intact C6-2B cells. Evidence for enhanced Gs-C coupling.

Forskolin directly stimulates adenylate cyclase activity and acts synergistically with receptor-mediated agonists which stimulate cyclic AMP production. We have previously observed that a 3-hr incubation of C6-2B rat astrocytoma cells with 6 nM cholera toxin in the presence of 1 microM forskolin results in cyclic AMP accumulation 9-fold greater than in the absence of forskolin. Since the action of cholera toxin is mediated by the stimulatory guanine nucleotide-binding regulatory component (GS) of the adenylate cyclase complex, we proposed that the mechanism by which forskolin augments hormone responses involves an enhanced coupling of GS with the adenylate cyclase catalytic component (C). In the present communication, we report the detailed characterization of the synergistic interaction between forskolin and cholera toxin as effectors of cyclic AMP accumulation in intact C6-2B cells. After a 3-hr incubation, maximal cholera toxin-stimulated cyclic AMP accumulation was 990 +/- 34 pmol/mg of protein. In the presence of 1 microM forskolin, the response to cholera toxin increased to 13,137 +/- 1,595 pmol of cyclic AMP/mg of protein. The half-maximally effective cholera toxin concentrations estimated by nonlinear least squares regression analysis determined in the absence or presence of 0.1 mM forskolin were 56.6 and 57.5 pM, respectively. The highly reproducible lag in forskolin-stimulated cyclic AMP accumulation in C6-2B cells was abolished by cholera toxin pretreatment, indicating a possible role for GS-associated GTPase in the mechanism of forskolin action. Cholera toxin treatment markedly augmented forskolin-stimulated cyclic AMP accumulation and shifted the forskolin concentration-response curve to the left approximately 1.5 log units. When C6-2B cells were treated for 1 min with 10 nM cholera toxin, the response to forskolin was significantly potentiated by 10 min. No significant increase in cellular cyclic AMP content in the absence of a forskolin challenge was apparent for up to 45 min. It appears that prior promotion of GS-C coupling by cholera toxin treatment enhances the ability of forskolin to stimulate cyclic AMP accumulation. Whether or not forskolin interacts (i.e., binds) exclusively to C remains to be proven. However, the actions of forskolin to stimulate cyclic AMP formation and potentiate agonist-stimulated cyclic AMP formation are modulated by the activity state of GS, and at least part of the response to forskolin is mediated by GS.

Adenosine Diphosphate Ribose↗

PubMed1976

[About the heterogeneity of the murine oncornavirus group-specific antigen gs-1 (author's transl)].

In isoelectric focusing of twofold gradienpturified and Tween 80-ether disrupted RLV the groupspecific antigen (gs-1) was found in 3 pH-zones (4,45-5,5; 5,65-6,0; 6,45-6,6). For the gs-1 from plasma und spleen cells of leukemic mice was shown heterogeneity by several methods: 1. Gs-1 from plasma showed in isoelectric focusing a scattering along the whole elution profile. 2. Agarimmunoelectrophoresis resulted in a longer precipitationline for gs-1 from plasma in comparison with gs-1 from spleen cells. 3. Polyacrylamidgelelectrophoresis with following immunodiffusion made evident the particularly discrete character of this heterogeneity: gs-1 from both materials were found in two main zones.

Animals↗

PubMed1984

ADP-ribosylation of Gs promotes the dissociation of its alpha and beta subunits.

We have utilized purified reactants and cofactors to examine the form of the stimulatory guanine nucleotide-binding regulatory component (Gs) of adenylate cyclase that serves as a substrate for ADP-ribosylation by cholera toxin; we have also investigated some of the consequences of that covalent modification. Activation of Gs with nonhydrolyzable analogs of GTP, which causes dissociation of its subunits, completely inhibits the toxin-catalyzed covalent modification. However, this effect cannot be explained by subunit dissociation, since activation of Gs by fluoride is not inhibitory and ADP ribosylation of the alpha (45,000-Da) subunit of Gs proceeds equally well in the presence and absence of the beta (35,000-Da) subunit. ADP-ribosylation of the alpha subunit of Gs decreases its apparent affinity for the beta subunit; however, the affinity of alpha and ADP-ribosyl-alpha for GTP appear to be approximately the same. ADP-ribosylation of Gs thus promotes the dissociation of its alpha and beta subunits. This effect may account for or contribute to the activation of adenylate cyclase by cholera toxin.

Adenosine Diphosphate Ribose↗

PubMed1994

Stimulatory guanine nucleotide binding protein in pig epidermis: transient increase of the 45KDA cholera toxin substrate (Gs alpha) in the tape stripping-induced hyperproliferative state.

Cholera toxin catalyzed the transfer of ADP-ribose from [alpha-32P] NAD to 45kDa protein in pig epidermis. Western blot analysis using anti-Gs alpha antibody identified the 45kDa protein to be Gs alpha. In contrast to pertussis toxin-catalyzed ADP-ribosylation of Gi alpha, the cholera toxin-catalyzed ADP-ribosylation was enhanced by the presence of Mg2+ in the reaction mixture. The cholera toxin-catalyzed ADP-ribosylation of the epidermal 45kDa membrane protein was significantly decreased, when samples were prepared from the cholera toxin-pretreated epidermis. The results, coupled with our previous report (Tsutsui and Iizuka 1990), indicate that pig epidermis contains functional G proteins (Gs and Gi), that affect the epidermal adenylate cyclase activity. Tape stripping-induced hyperproliferative epidermis showed an increased cholera toxin-catalyzed ADP-ribosylation of the 45kDa protein (Gs alpha) at 12-24 h following the tape stripping. Immunoblot analysis, however, showed no remarkable change in the level of Gs alpha compared with non-stripping controls. There was no significant difference in the level of the pertussis toxin-induced ADP-ribosylation of 40kDa protein (Gi alpha) in the tape-stripped epidermis. Immunoblot analysis showed no change in Gi content, either. Forskolin-induced cyclic AMP accumulation was markedly increased in the tape stripping-induced hyperproliferative epidermis. Cholera toxin-induced cyclic AMP accumulation was slightly increased, but this was not statistically significant. These results indicate that the alteration of Gs that is documented by cholera toxin-catalyzed ADP-ribosylation, is among the functional derangements of adenylate cyclase of tape stripping-induced hyperproliferative epidermis.

Adenosine Diphosphate Ribose↗

PubMed2006

Gbetagamma that interacts with adenylyl cyclase in opioid tolerance originates from a Gs protein.

We previously demonstrated that chronic morphine induces a change in G protein coupling by the mu opioid receptor (MOR) from Gi/o to Gs, concurrent with the instatement of an interaction between Gbetagamma and adenylyl cyclase types II and IV. These two signaling changes confer excitatory effects on the cell in place of the typical inhibition by opioids and are associated with morphine tolerance and dependence. Both signaling changes and these behavioral manifestations of chronic morphine are attenuated by cotreatment with ultra-low-dose naloxone. In the present work, using striatum from chronic morphine-treated rats, we isotyped the Gbeta within Gs and Go heterotrimers that coupled to MOR and compared these to the Gbeta isotype of the Gbetagamma that interacted with adenylyl cyclase II or IV after chronic morphine treatment. Isotyping results show that chronic morphine causes a Gs heterotrimer associated with MOR to release its Gbetagamma to interact with adenylyl cyclase. These data suggest that the switch to Gs coupling by MOR in response to chronic morphine, which is attenuated by ultra-low-dose opioid antagonist cotreatment, leads to a two-pronged stimulation of adenylyl cyclase utilizing both Galpha and Gbetagamma subunits of the Gs protein novel to this receptor.

Adenylyl Cyclases↗

PubMed2000

Activating Gs(alpha) mutation in intramuscular myxomas with and without fibrous dysplasia of bone.

Activating missense mutations in the Arg 201 codon of the gene encoding the alpha subunit of Gs, the G protein that stimulates cAMP formation, have been recognized as the cause of many endocrine diseases, McCune-Albright syndrome and isolated fibrous dysplasia of bone. On the other hand, intramuscular myxomas with fibrous dysplasia, so-called Mazabraud's syndrome, have been sporadically reported, but it has not been confirmed whether intramuscular myxoma, with or without fibrous dysplasia, is associated with the Gs(alpha) mutations. We investigated the presence of the Gs(alpha) mutations in intramuscular myxomas with or without fibrous dysplasia by a PCR-SSCP assay, using formalin-fixed, paraffin-embedded tissues. In five of the six intramuscular myxomas (three with and two without fibrous dysplasia), point mutations were detected as aberrant bands by SSCP, which were confirmed by a subsequent sequence analysis (three Arg to His and two Arg to Cys). This result suggests that the Gs(alpha) mutations are related to tumorigenesis in intramuscular myxoma and that intramuscular myxoma is one of the diseases induced by abnormal Gs(alpha) protein.

Adult↗

PubMed2002

Juxta-articular myxoma and intramuscular myxoma are two distinct entities. Activating Gs alpha mutation at Arg 201 codon does not occur in juxta-articular myxoma.

Juxta-articular myxoma is a rare myxoid tumor of soft tissue that bears a close histologic resemblance to intramuscular myxoma but is distinguished from the latter by its clinical setting and behavior. Activating missense mutations at the Arg 201 codon of the Gs alpha gene ultimately leading to increased levels of cyclic adenosine monophosphate have been implicated in McCune-Albright syndrome and sporadic fibrous dysplasia of bone. Recently, we have demonstrated that the same Gs alpha mutations occur in intramuscular myxomas associated with fibrous dysplasia of bone (Mazabraud's syndrome) as well as in sporadic intramuscular myxoma. The overlapping histologic appearances of juxta-articular myxoma and intramuscular myxoma prompted us to investigate whether there is a relationship between the two entities. We studied this possibility by looking for Gs alpha mutations in juxta-articular myxoma using polymerase chain reaction (PCR) to amplify appropriate genomic DNA fragments extracted from formalin-fixed, paraffin-embedded specimens of five juxta-articular myxomas, followed by single-strand conformation polymorphism analysis. Using these techniques, no aberrant bands were detected in any of the five juxta-articular myxomas, indicating that they lack Gs alpha mutations. Moreover, DNA sequencing of the PCR products of two JAMs showed no abnormalities. We conclude that juxta-articular myxomas, in contrast to intramuscular myxomas, do not involve Arg 201 mutations of the Gs alpha gene, indicating that they represent distinct entities with different underlying molecular mechanisms.

Adult↗