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• W2073006091 abstract "G protein-coupled receptor agonists initiate a cascade of signaling events in neonatal rat ventricular myocytes that culminates in changes in gene expression and cell growth characteristic of hypertrophy. These responses have been previously shown to be dependent on Gq and Ras. Rho, a member of the Ras superfamily of GTPases, regulates cytoskeletal rearrangement and transcriptional activation of the c-fos serum response element. Immunofluorescence staining of cardiomyocytes shows that Rho is present and predominantly cytosolic. We used two inhibitors of Rho function, dominant negative N19RhoA and Clostridium botulinum C3 transferase, to examine the possible requirement for Rho in α1-adrenergic receptor-mediated hypertrophy. Both inhibitors markedly attenuated atrial natriuretic factor (ANF) reporter gene expression induced by α1-adrenergic receptor stimulation with phenylephrine, and virtually abolished the increase in ANF reporter gene expression induced by GTPase-deficient Gαq. These effects were reproduced with the myosin light chain-2 reporter gene. Notably, N19RhoA did not block the ability of activated Ras to induce ANF and myosin light chain-2 reporter gene expression. Furthermore, activation of the extracellular signal-regulated kinase by phenylephrine was not blocked by N19RhoA, nor was it stimulated by an activated mutant of RhoA. Since activated RhoA and Ras produce a large synergistic effect on ANF-luciferase gene expression, we conclude that Rho functions in a pathway separate from but complementary to Ras. Our results provide direct evidence that Rho is an effector of Gαq signaling and suggest for the first time that a low molecular weight GTPase other than Ras is involved in regulating myocardial cell growth and gene expression in response to heterotrimeric G protein-linked receptor activation. G protein-coupled receptor agonists initiate a cascade of signaling events in neonatal rat ventricular myocytes that culminates in changes in gene expression and cell growth characteristic of hypertrophy. These responses have been previously shown to be dependent on Gq and Ras. Rho, a member of the Ras superfamily of GTPases, regulates cytoskeletal rearrangement and transcriptional activation of the c-fos serum response element. Immunofluorescence staining of cardiomyocytes shows that Rho is present and predominantly cytosolic. We used two inhibitors of Rho function, dominant negative N19RhoA and Clostridium botulinum C3 transferase, to examine the possible requirement for Rho in α1-adrenergic receptor-mediated hypertrophy. Both inhibitors markedly attenuated atrial natriuretic factor (ANF) reporter gene expression induced by α1-adrenergic receptor stimulation with phenylephrine, and virtually abolished the increase in ANF reporter gene expression induced by GTPase-deficient Gαq. These effects were reproduced with the myosin light chain-2 reporter gene. Notably, N19RhoA did not block the ability of activated Ras to induce ANF and myosin light chain-2 reporter gene expression. Furthermore, activation of the extracellular signal-regulated kinase by phenylephrine was not blocked by N19RhoA, nor was it stimulated by an activated mutant of RhoA. Since activated RhoA and Ras produce a large synergistic effect on ANF-luciferase gene expression, we conclude that Rho functions in a pathway separate from but complementary to Ras. Our results provide direct evidence that Rho is an effector of Gαq signaling and suggest for the first time that a low molecular weight GTPase other than Ras is involved in regulating myocardial cell growth and gene expression in response to heterotrimeric G protein-linked receptor activation. INTRODUCTIONStimulation of the α1-adrenergic receptor in neonatal rat ventricular myocytes induces a hypertrophic response accompanied by activation of a subset of immediate early genes (e.g. c-fos, c-jun, and egr-1), up-regulation of a constitutively expressed contractile protein gene (myosin light chain-2 (MLC-2)), 1The abbreviations used are: MLC-2myosin light chain-2ANFatrial natriuretic factorMAPmitogen-activated proteinPEphenylephrineSREserum response elementERKextracellular signalregulated kinaseJNKc-Jun NH2-terminal kinaseHAhemagglutininGAPGTPase-activating proteinPIP2phosphatidylinositol 4,5-bisphosphate. and reactivation of embryonic genes (e.g. atrial natriuretic factor (ANF), β-myosin heavy chain, and skeletal α-actin). There are also associated morphological changes, specifically increases in cell size and volume, and organization of myofilaments into sarcomeric units (1Simpson P. J. Clin. Invest. 1983; 72: 732-738Crossref PubMed Scopus (546) Google Scholar, 2Bishopric N.H. Simpson P.C. Ordahl C.P. J. Clin. Invest. 1987; 80: 1194-1199Crossref PubMed Scopus (157) Google Scholar, 3Lee H.R. Henderson S.A. Reynolds R. Dunnmon P. Yuan D. Chien K.R. J. Biol. Chem. 1988; 263: 7352-7358Abstract Full Text PDF PubMed Google Scholar, 4Waspe L.E. Ordahl C.P. Simpson P.C. J. Clin. Invest. 1990; 85: 1206-1214Crossref PubMed Scopus (155) Google Scholar, 5Chien K.R. Knowlton K.U. Zhu H. Chien S. FASEB J. 1991; 5: 3037-3046Crossref PubMed Scopus (694) Google Scholar, 6Knowlton K.U. Baracchini E. Ross R.S. Harris A.N. Henderson S.A. Evans S.M. Glembotski C.C. Chien K.R. J. Biol. Chem. 1991; 266: 7759-7768Abstract Full Text PDF PubMed Google Scholar, 7Knowlton K.U. Michel M.C. Itani M. Shubeita H.E. Ishihara K. Brown J.H. Chien K.R. J. Biol. Chem. 1993; 268: 15374-15380Abstract Full Text PDF PubMed Google Scholar).While many of the features of myocardial hypertrophy can be reproduced in vitro, the precise molecular signaling pathways regulating these hypertrophic responses have not yet been fully elucidated. Several lines of evidence indicate that α1-adrenergic receptor-induced hypertrophy is mediated by both Gq- and Ras-dependent pathways (8Thorburn A. Thorburn J. Chen S.-Y. Powers S. Shubeita H.E. Feramisco J.R. Chien K.R. J. Biol. Chem. 1993; 268: 2244-2249Abstract Full Text PDF PubMed Google Scholar, 9LaMorte V.J. Thorburn J. Absher D. Spiegel A.M. Brown J.H. Chien K.R. Feramisco J.R. Knowlton K.U. J. Biol. Chem. 1994; 269: 13490-13496Abstract Full Text PDF PubMed Google Scholar), and it has been suggested that Gαq and Ras regulate independent pathways leading from α1-adrenergic receptor activation to ANF gene expression (9LaMorte V.J. Thorburn J. Absher D. Spiegel A.M. Brown J.H. Chien K.R. Feramisco J.R. Knowlton K.U. J. Biol. Chem. 1994; 269: 13490-13496Abstract Full Text PDF PubMed Google Scholar). The Ras/mitogen-activated protein (MAP) kinase cascade can mediate downstream responses to α1-adrenergic agonists (10Thorburn J. McMahon M. Thorburn A. J. Biol. Chem. 1994; 269: 30580-30586Abstract Full Text PDF PubMed Google Scholar, 11Thorburn J. Frost J.A. Thorburn A. J. Cell Biol. 1994; 126: 1565-1572Crossref PubMed Scopus (181) Google Scholar, 12Gillespie-Brown J. Fuller S.J. Bogoyevitch M.A. Cowley S. Sugden P.H. J. Biol. Chem. 1995; 270: 28092-28096Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 13Bogoyevitch M.A. Marshall C.J. Sugden P.H. J. Biol. Chem. 1995; 270: 26303-26310Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 14Post G.R. Goldstein D. Thuerauf D. Glembotski C.C. Brown J.H. J. Biol. Chem. 1996; 271: 8452-8457Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 15Glennon P.E. Kaddoura S. Sale E.M. Sale G.J. Fuller S.J. Sugden P.H. Circ. Res. 1996; 78: 954-961Crossref PubMed Scopus (196) Google Scholar), but MAP kinase/ERK is not required for the morphological changes induced by PE (11Thorburn J. Frost J.A. Thorburn A. J. Cell Biol. 1994; 126: 1565-1572Crossref PubMed Scopus (181) Google Scholar) and ERK activation is not sufficient to induce hypertrophic responses (14Post G.R. Goldstein D. Thuerauf D. Glembotski C.C. Brown J.H. J. Biol. Chem. 1996; 271: 8452-8457Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Likewise, expression of constitutively activated Gαq alone is not sufficient to induce the typical changes in cell size and cellular organization seen with α1-adrenergic receptor stimulation or Ras (9LaMorte V.J. Thorburn J. Absher D. Spiegel A.M. Brown J.H. Chien K.R. Feramisco J.R. Knowlton K.U. J. Biol. Chem. 1994; 269: 13490-13496Abstract Full Text PDF PubMed Google Scholar). Thus the activation of both Ras and Gq signaling pathways may be required to induce the genetic and morphological responses associated with hypertrophy.Recently, the Rho family of low molecular weight GTP-binding proteins (Cdc42, Rac, Rho) has been shown to participate in the regulation of various kinase (16Coso O.A. Chiariello M. Yu J.C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1559) Google Scholar, 17Minden A. Lin A. Claret F.-X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1443) Google Scholar, 18Vojtek A.B. Cooper J.A. Cell. 1995; 82: 527-529Abstract Full Text PDF PubMed Scopus (253) Google Scholar) and cytoskeletal pathways (19Ridley A.J. Hall A. Cell. 1992; 70: 389-399Abstract Full Text PDF PubMed Scopus (3797) Google Scholar, 20Ridley A.J. Paterson H.F. Johnston C.L. Diekmann D. Hall A. Cell. 1992; 70: 401-410Abstract Full Text PDF PubMed Scopus (3049) Google Scholar, 21Nobes C.D. Hall A. Cell. 1995; 81: 53-62Abstract Full Text PDF PubMed Scopus (3698) Google Scholar). These proteins are well accepted as regulators of the actin cytoskeleton and are involved in the formation of filopodia, lamellipodia, stress fibers, and focal adhesions. In addition to these cytoskeletal effects, Rho has recently been demonstrated to regulate activation of the serum response element (SRE) in the c-fos promoter (22Hill C.S. Wynne J. Treisman R. Cell. 1995; 81: 1159-1170Abstract Full Text PDF PubMed Scopus (1199) Google Scholar). Given the prominent effects of Rho on both gene expression and morphology in other systems, we hypothesized that this low molecular weight GTPase might also have a functional role in myocardial cell regulation.In this study we examined the involvement of Rho in the α1-adrenergic receptor-activated hypertrophic responses. We show that Rho is required for PE-induced ANF and MLC-2 gene expression. Furthermore, while the induction of ANF and MLC-2 gene expression by activated Gαq is demonstrated to be dependent on Rho function, the response to oncogenic Ras is not. Our data suggest that the α1-adrenergic receptor and heterotrimeric Gq protein transduce signals through Rho, and that Rho functions in a pathway separate from but complementary to Ras in mediating genetic responses in myocardial hypertrophy.DISCUSSIONEvidence implicating Rho in G protein-coupled receptor-induced gene expression was recently presented in a study published by Treisman's laboratory. These authors demonstrated that in NIH 3T3 cells a constitutively activated Rho mutant induced transcriptional activation of the c-fos SRE; in addition lysophosphatidic acid- and AlF4−-induced signaling to c-fos SRE activation was inhibited by C3 transferase (22Hill C.S. Wynne J. Treisman R. Cell. 1995; 81: 1159-1170Abstract Full Text PDF PubMed Scopus (1199) Google Scholar). Our work in cardiomyocytes further implicates Rho in mediating the effects of G protein-coupled receptor agonists on transcriptional activation and, more specifically, identifies the cardiac-specific ANF and MLC-2 genes as targets for Rho-dependent activation.Our finding that inhibition of Rho function blocks PE-induced activation of the ANF- and MLC-2-luciferase reporter genes implicates Rho in mediating genetic responses to α1-adrenergic receptor stimulation. The fact that the inhibition was incomplete could reflect insufficient levels of expression of N19RhoA, or alternatively, PE signaling through an additional pathway that is independent of Rho function. The latter alternative is consistent with data from previous studies, which suggested the existence of two distinct pathways mediating PE-induced gene expression (9LaMorte V.J. Thorburn J. Absher D. Spiegel A.M. Brown J.H. Chien K.R. Feramisco J.R. Knowlton K.U. J. Biol. Chem. 1994; 269: 13490-13496Abstract Full Text PDF PubMed Google Scholar). One of these pathways is mediated by Gαq, and the other by Ras. Interestingly, the effect of coexpressing N19RhoA with activated Gαq or oncogenic Ras differentiated these pathways. Whereas N19RhoA blocked Gαq-induced ANF- and MLC-2-luciferase gene expression, it had no apparent inhibitory effect on Ras-induced gene expression. In addition, PE-induced activation of kinase cascades downstream of Ras (ERK and JNK) was unaffected by N19RhoA. Our data therefore suggest that Rho is required in Gαq-mediated signaling, but not in Ras-mediated events. Further support for the existence of two distinct pathways come from our demonstration that there is a synergistic effect of oncogenic L61Ras and either activated Gαq or L63RhoA on ANF-luciferase gene expression.The level at which the separate Ras and Rho signaling pathways converge to give a synergistic increase in ANF-luciferase expression is not yet clear. Microinjection studies in fibroblasts suggest an ordered set of interactions between Ras and the Rho family GTPases, namely that Ras is upstream of and required for activation of Rac, which in turn activates Rho (21Nobes C.D. Hall A. Cell. 1995; 81: 53-62Abstract Full Text PDF PubMed Scopus (3698) Google Scholar, 34Chant J. Stowers L. Cell. 1995; 81: 1-4Abstract Full Text PDF PubMed Scopus (260) Google Scholar). Coordination of Ras- and Rho-mediated signaling pathways could occur through the interaction between p120RasGAP and p190RhoGAP proteins (35Settleman J. Albright C.F. Foster L.C. Weinberg R.A. Nature. 1992; 359: 153-154Crossref PubMed Scopus (249) Google Scholar, 36Bryant S.S. Briggs S. Smithgall T.E. Martin G.A. McCormick F. Chang J.-H. Parsons S.J. Jove R. J. Biol. Chem. 1995; 270: 17947-17952Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar), through RalGDS (37Jullien-Flores V. Dorseuil O. Romero F. Letourneur F. Saragosti S. Berger R. Tavitian A. Gacon G. Camonis J.H. J. Biol. Chem. 1995; 270: 22473-22477Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 38Cantor S.B. Urano T. Feig L.A. Mol. Cell. Biol. 1995; 15: 4578-4584Crossref PubMed Scopus (260) Google Scholar), through Ras guanine nucleotide exchange proteins (39McCollam L. Bonfini L. Karlovich C.A. Conway B.R. Kozma L.M. Banerjee U. Czech M.P. J. Biol. Chem. 1995; 270: 15954-15957Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar), or through phosphatidylinositol 3-kinase (40Rodriguez-Viciana P. Warne P.H. Dhand R. Vanhaesebroeck B. Gout I. Fry M.J. Waterfield M.D. Downward J. Nature. 1994; 370: 527-532Crossref PubMed Scopus (1716) Google Scholar, 41Zheng Y. Bagrodia S. Cerione R.A. J. Biol. Chem. 1994; 269: 18727-18730Abstract Full Text PDF PubMed Google Scholar, 42Tolias K.F. Cantley L.C. Carpenter C.L. J. Biol. Chem. 1995; 270: 17656-17659Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar). However, our results suggest that Rho is activated by PE and Gαq independent of Ras. In addition, Rho does not interact with the Ras signaling pathway via activation of MAP kinases.Where in the signaling pathway Rho functions is under current investigation. One mechanism by which Rho might affect Gq-dependent hypertrophic responses is by regulating the cellular level of phosphatidylinositol 4,5-bisphosphate (PIP2). This possibility is suggested by the finding that in fibroblasts Rho regulates the activity of phosphatidylinositol 4-phosphate 5-kinase (43Chong L.D. Traynor-Kaplan A. Bokoch G.M. Schwartz M.A. Cell. 1994; 79: 507-513Abstract Full Text PDF PubMed Scopus (592) Google Scholar), an enzyme that is critical for the production of PIP2, the substrate for Gq-activated phospholipase C. If RhoA regulates the production of PIP2 in cardiac myocytes, the amount of substrate available for phospholipase C hydrolysis and consequent protein kinase C activation and Ca2+ mobilization initiated by Gq-linked α1-adrenergic receptor activation might be regulated by this pathway. Alterations in PIP2 levels may also affect the activity of other phospholipid-metabolizing enzymes, such as phospholipase D, which has been shown to be regulated by Rho (44Bowman E.P. Uhlinger D.J. Lambeth J.D. J. Biol. Chem. 1993; 268: 21509-21512Abstract Full Text PDF PubMed Google Scholar, 45Malcolm K.C. Ross A.H. Qiu R.-G. Symons M. Exton J.H. J. Biol. Chem. 1994; 269: 25951-25954Abstract Full Text PDF PubMed Google Scholar).In addition, Rho has been postulated to be regulated by and/or to modulate tyrosine kinase activities (46Kumagai N. Morii N. Fujisawa K. Nemoto Y. Narumiya S. J. Biol. Chem. 1993; 268: 24535-24538Abstract Full Text PDF PubMed Google Scholar, 47Moolenaar W.H. J. Biol. Chem. 1995; 270: 12949-12952Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar). Targets of Rho-dependent tyrosine phosphorylation include the p125 focal adhesion kinase (p125FAK), which is itself a tyrosine kinase, and paxillin (48Rankin S. Morii N. Narumiya S. Rozengurt E. FEBS Lett. 1994; 354: 315-319Crossref PubMed Scopus (131) Google Scholar, 49Seckl M.J. Morii N. Narumiya S. Rozengurt E. J. Biol. Chem. 1995; 270: 6984-6990Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Several serine-threonine protein kinases have also recently been cloned and characterized as Rho effectors (50Leung T. Manser E. Tan L. Lim L. J. Biol. Chem. 1995; 270: 29051-29054Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar, 51Watanabe G. Saito Y. Madaule P. Ishizaki T. Fujisawa K. Morii N. Mukai H. Ono Y. Kakizuka A. Narumiya S. Science. 1996; 271: 645-648Crossref PubMed Scopus (348) Google Scholar, 52Amano M. Mukai H. Ono Y. Chihara K. Matsui T. Hamajima Y. Okawa K. Iwamatsu A. Kaibuchi K. Science. 1996; 271: 648-650Crossref PubMed Scopus (395) Google Scholar), and the study of their activation and possible kinase cascades that they influence will further aid our understanding of the role of Rho in regulating the hypertrophic response.It is well established that, in selected systems, Rho function is required to effect changes in cellular morphology induced by G protein-coupled receptors. Jalink et al. (53Jalink K. van Corven E.J. Hengeveld T. Morii N. Narumiya S. Moolenaar W.H. J. Cell Biol. 1994; 126: 801-810Crossref PubMed Scopus (573) Google Scholar) demonstrated that ADP-ribosylation of Rho inhibits neurite retraction and neuronal cell rounding induced by lysophosphatidic acid and thrombin. In addition, Tigyi et al. (54Tigyi G. Fischer D.J. Sebok A. Yang C. Dyer D.L. Miledi R. J. Neurochem. 1996; 66: 537-548Crossref PubMed Scopus (184) Google Scholar) recently reported that lysophosphatidic acid-induced neurite retraction in PC12 cells is regulated by phosphoinositide-Ca2+ signaling and is blocked by ADP-ribosylation of Rho. These effects are pertussis toxin-insensitive, suggesting the involvement of a Gq pathway. Rho-dependent cytoskeletal responses might also be activated through Gq-coupled receptors in cardiac myocytes and serve as triggers for subsequent events involved in the establishment of a hypertrophic phenotype. For example, activation of tyrosine kinases associated with the actin cytoskeleton (e.g. p125FAK) may serve to signal from G protein-coupled receptors to downstream kinase cascades, as observed in integrin signaling pathways (55Schlaepfer D.D. Hanks S.K. Hunter T. van der Geer P. Nature. 1994; 372: 786-791Crossref PubMed Scopus (1437) Google Scholar).Another pertussis toxin-insensitive protein, G12, has been previously demonstrated to possess transforming activity (56Aaronson S.A. Science. 1991; 254: 1146-1153Crossref PubMed Scopus (1150) Google Scholar, 57Xu N. Bradley L. Ambdukar I. Gutkind S. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 6741-6745Crossref PubMed Scopus (174) Google Scholar, 58Jiang H. Wu D. Simon M.I. FEBS Lett. 1993; 330: 319-322Crossref PubMed Scopus (101) Google Scholar). We recently presented evidence that G12 can couple to low molecular weight GTPases and participates in thrombin-stimulated growth responses (30Collins L.R. Minden A. Karin M. Brown J.H. J. Biol. Chem. 1996; 271: 17349-17353Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 59Aragay A.M. Collins L.R. Post G.R. Watson A.J. Feramisco J.R. Brown J.H. Simon M.I. J. Biol. Chem. 1995; 270: 20073-20077Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 60Post G.R. Collins L.R. Kennedy E.D. Moskowitz S.A. Aragay A.M. Goldstein D. Brown J.H. Mol. Biol. Cell. 1996; 7: 1679-1690Crossref PubMed Scopus (66) Google Scholar). In addition, activated Gα12 and/or the related Gα13 stimulate stress fiber formation, focal adhesion assembly and Na+-H+ exchange through Rho-dependent mechanisms (61Buhl A.M. Johnson N.L. Dhanasekaran N. Johnson G.L. J. Biol. Chem. 1995; 270: 24631-24634Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar, 62Hooley R. Yu C.-Y. Symons M. Barber D.L. J. Biol. Chem. 1996; 271: 6152-6158Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Thus, G12 is another possible transducer of information from the α1-adrenergic receptor to the small G protein Rho.In this study we provide the first direct evidence that Rho is required for Gq-mediated signaling. Our findings demonstrate a specific role for Rho in regulating α1-adrenergic receptor-mediated activation of ANF and MLC-2 gene expression, and show that in cardiac myocytes, Rho function is required for Gαq but not for Ras-induced responses. These results suggest that growth regulation through Gq-coupled receptors involves activation of Rho-dependent as well as Ras-dependent processes. INTRODUCTIONStimulation of the α1-adrenergic receptor in neonatal rat ventricular myocytes induces a hypertrophic response accompanied by activation of a subset of immediate early genes (e.g. c-fos, c-jun, and egr-1), up-regulation of a constitutively expressed contractile protein gene (myosin light chain-2 (MLC-2)), 1The abbreviations used are: MLC-2myosin light chain-2ANFatrial natriuretic factorMAPmitogen-activated proteinPEphenylephrineSREserum response elementERKextracellular signalregulated kinaseJNKc-Jun NH2-terminal kinaseHAhemagglutininGAPGTPase-activating proteinPIP2phosphatidylinositol 4,5-bisphosphate. and reactivation of embryonic genes (e.g. atrial natriuretic factor (ANF), β-myosin heavy chain, and skeletal α-actin). There are also associated morphological changes, specifically increases in cell size and volume, and organization of myofilaments into sarcomeric units (1Simpson P. J. Clin. Invest. 1983; 72: 732-738Crossref PubMed Scopus (546) Google Scholar, 2Bishopric N.H. Simpson P.C. Ordahl C.P. J. Clin. Invest. 1987; 80: 1194-1199Crossref PubMed Scopus (157) Google Scholar, 3Lee H.R. Henderson S.A. Reynolds R. Dunnmon P. Yuan D. Chien K.R. J. Biol. Chem. 1988; 263: 7352-7358Abstract Full Text PDF PubMed Google Scholar, 4Waspe L.E. Ordahl C.P. Simpson P.C. J. Clin. Invest. 1990; 85: 1206-1214Crossref PubMed Scopus (155) Google Scholar, 5Chien K.R. Knowlton K.U. Zhu H. Chien S. FASEB J. 1991; 5: 3037-3046Crossref PubMed Scopus (694) Google Scholar, 6Knowlton K.U. Baracchini E. Ross R.S. Harris A.N. Henderson S.A. Evans S.M. Glembotski C.C. Chien K.R. J. Biol. Chem. 1991; 266: 7759-7768Abstract Full Text PDF PubMed Google Scholar, 7Knowlton K.U. Michel M.C. Itani M. Shubeita H.E. Ishihara K. Brown J.H. Chien K.R. J. Biol. Chem. 1993; 268: 15374-15380Abstract Full Text PDF PubMed Google Scholar).While many of the features of myocardial hypertrophy can be reproduced in vitro, the precise molecular signaling pathways regulating these hypertrophic responses have not yet been fully elucidated. Several lines of evidence indicate that α1-adrenergic receptor-induced hypertrophy is mediated by both Gq- and Ras-dependent pathways (8Thorburn A. Thorburn J. Chen S.-Y. Powers S. Shubeita H.E. Feramisco J.R. Chien K.R. J. Biol. Chem. 1993; 268: 2244-2249Abstract Full Text PDF PubMed Google Scholar, 9LaMorte V.J. Thorburn J. Absher D. Spiegel A.M. Brown J.H. Chien K.R. Feramisco J.R. Knowlton K.U. J. Biol. Chem. 1994; 269: 13490-13496Abstract Full Text PDF PubMed Google Scholar), and it has been suggested that Gαq and Ras regulate independent pathways leading from α1-adrenergic receptor activation to ANF gene expression (9LaMorte V.J. Thorburn J. Absher D. Spiegel A.M. Brown J.H. Chien K.R. Feramisco J.R. Knowlton K.U. J. Biol. Chem. 1994; 269: 13490-13496Abstract Full Text PDF PubMed Google Scholar). The Ras/mitogen-activated protein (MAP) kinase cascade can mediate downstream responses to α1-adrenergic agonists (10Thorburn J. McMahon M. Thorburn A. J. Biol. Chem. 1994; 269: 30580-30586Abstract Full Text PDF PubMed Google Scholar, 11Thorburn J. Frost J.A. Thorburn A. J. Cell Biol. 1994; 126: 1565-1572Crossref PubMed Scopus (181) Google Scholar, 12Gillespie-Brown J. Fuller S.J. Bogoyevitch M.A. Cowley S. Sugden P.H. J. Biol. Chem. 1995; 270: 28092-28096Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 13Bogoyevitch M.A. Marshall C.J. Sugden P.H. J. Biol. Chem. 1995; 270: 26303-26310Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 14Post G.R. Goldstein D. Thuerauf D. Glembotski C.C. Brown J.H. J. Biol. Chem. 1996; 271: 8452-8457Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 15Glennon P.E. Kaddoura S. Sale E.M. Sale G.J. Fuller S.J. Sugden P.H. Circ. Res. 1996; 78: 954-961Crossref PubMed Scopus (196) Google Scholar), but MAP kinase/ERK is not required for the morphological changes induced by PE (11Thorburn J. Frost J.A. Thorburn A. J. Cell Biol. 1994; 126: 1565-1572Crossref PubMed Scopus (181) Google Scholar) and ERK activation is not sufficient to induce hypertrophic responses (14Post G.R. Goldstein D. Thuerauf D. Glembotski C.C. Brown J.H. J. Biol. Chem. 1996; 271: 8452-8457Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Likewise, expression of constitutively activated Gαq alone is not sufficient to induce the typical changes in cell size and cellular organization seen with α1-adrenergic receptor stimulation or Ras (9LaMorte V.J. Thorburn J. Absher D. Spiegel A.M. Brown J.H. Chien K.R. Feramisco J.R. Knowlton K.U. J. Biol. Chem. 1994; 269: 13490-13496Abstract Full Text PDF PubMed Google Scholar). Thus the activation of both Ras and Gq signaling pathways may be required to induce the genetic and morphological responses associated with hypertrophy.Recently, the Rho family of low molecular weight GTP-binding proteins (Cdc42, Rac, Rho) has been shown to participate in the regulation of various kinase (16Coso O.A. Chiariello M. Yu J.C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1559) Google Scholar, 17Minden A. Lin A. Claret F.-X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1443) Google Scholar, 18Vojtek A.B. Cooper J.A. Cell. 1995; 82: 527-529Abstract Full Text PDF PubMed Scopus (253) Google Scholar) and cytoskeletal pathways (19Ridley A.J. Hall A. Cell. 1992; 70: 389-399Abstract Full Text PDF PubMed Scopus (3797) Google Scholar, 20Ridley A.J. Paterson H.F. Johnston C.L. Diekmann D. Hall A. Cell. 1992; 70: 401-410Abstract Full Text PDF PubMed Scopus (3049) Google Scholar, 21Nobes C.D. Hall A. Cell. 1995; 81: 53-62Abstract Full Text PDF PubMed Scopus (3698) Google Scholar). These proteins are well accepted as regulators of the actin cytoskeleton and are involved in the formation of filopodia, lamellipodia, stress fibers, and focal adhesions. In addition to these cytoskeletal effects, Rho has recently been demonstrated to regulate activation of the serum response element (SRE) in the c-fos promoter (22Hill C.S. Wynne J. Treisman R. Cell. 1995; 81: 1159-1170Abstract Full Text PDF PubMed Scopus (1199) Google Scholar). Given the prominent effects of Rho on both gene expression and morphology in other systems, we hypothesized that this low molecular weight GTPase might also have a functional role in myocardial cell regulation.In this study we examined the involvement of Rho in the α1-adrenergic receptor-activated hypertrophic responses. We show that Rho is required for PE-induced ANF and MLC-2 gene expression. Furthermore, while the induction of ANF and MLC-2 gene expression by activated Gαq is demonstrated to be dependent on Rho function, the response to oncogenic Ras is not. Our data suggest that the α1-adrenergic receptor and heterotrimeric Gq protein transduce signals through Rho, and that Rho functions in a pathway separate from but complementary to Ras in mediating genetic responses in myocardial hypertrophy." @default.
• W2073006091 created "2016-06-24" @default.
• W2073006091 creator A5036204802 @default.
• W2073006091 creator A5045287779 @default.
• W2073006091 creator A5067330064 @default.
• W2073006091 creator A5069061285 @default.
• W2073006091 date "1996-12-01" @default.
• W2073006091 modified "2023-10-14" @default.
• W2073006091 title "Rho Is Required for Gαq and α1-Adrenergic Receptor Signaling in Cardiomyocytes" @default.
• W2073006091 cites W1481203098 @default.
• W2073006091 cites W1482605042 @default.
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