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W2003160212 abstract "The role of activating protein-1 (AP-1) in muscle cells is currently equivocal. While some studies propose that AP-1 is inhibitory for myogenesis, others implicate a positive role in this process. We tested whether this variation may be due to different properties of the AP-1 subunit composition in differentiating cells. Using Western analysis we show that c-Jun, Fra-2, and JunD are expressed throughout the time course of differentiation. Phosphatase assays indicate that JunD and Fra-2 are phosphorylated in muscle cells and that at least two isoforms of each are expressed in muscle cells. Electrophoretic mobility shift assays combined with antibody supershifts indicate the appearance of Fra-2 as a major component of the AP-1 DNA binding complex in differentiating cells. In this context it appears that Fra-2 heterodimerizes with c-Jun and JunD. Studying the c-jun enhancer in reporter gene assays we observed that the muscle transcription factors MEF2A and MyoD can contribute to robust transcriptional activation of the c-jun enhancer. In differentiating muscle cells mutation of the MEF2 site reduces transactivation of the c-jun enhancer and MEF2A is the predominant MEF2 isoform binding to this cis element. Transcriptional activation of an AP-1 site containing reporter gene (TRE-Luc) is enhanced under differentiation conditions compared with growth conditions in C2C12 muscle cells. Further studies indicate that Fra-2 containing AP-1 complexes can transactivate the MyoD enhancer/promoter. Thus, an AP-1 complex containing Fra-2 and c-Jun or JunD is consistent with muscle differentiation, indicating that AP-1 function during myogenesis is dependent on its subunit composition. The role of activating protein-1 (AP-1) in muscle cells is currently equivocal. While some studies propose that AP-1 is inhibitory for myogenesis, others implicate a positive role in this process. We tested whether this variation may be due to different properties of the AP-1 subunit composition in differentiating cells. Using Western analysis we show that c-Jun, Fra-2, and JunD are expressed throughout the time course of differentiation. Phosphatase assays indicate that JunD and Fra-2 are phosphorylated in muscle cells and that at least two isoforms of each are expressed in muscle cells. Electrophoretic mobility shift assays combined with antibody supershifts indicate the appearance of Fra-2 as a major component of the AP-1 DNA binding complex in differentiating cells. In this context it appears that Fra-2 heterodimerizes with c-Jun and JunD. Studying the c-jun enhancer in reporter gene assays we observed that the muscle transcription factors MEF2A and MyoD can contribute to robust transcriptional activation of the c-jun enhancer. In differentiating muscle cells mutation of the MEF2 site reduces transactivation of the c-jun enhancer and MEF2A is the predominant MEF2 isoform binding to this cis element. Transcriptional activation of an AP-1 site containing reporter gene (TRE-Luc) is enhanced under differentiation conditions compared with growth conditions in C2C12 muscle cells. Further studies indicate that Fra-2 containing AP-1 complexes can transactivate the MyoD enhancer/promoter. Thus, an AP-1 complex containing Fra-2 and c-Jun or JunD is consistent with muscle differentiation, indicating that AP-1 function during myogenesis is dependent on its subunit composition. The activating protein-1 (AP-1) 1The abbreviations used are: AP-1activating protein-1TRE12-O-tetradecanoylphorbol-13-acetate response elementMRFmyogenic regulatory factorMEFmyocyte enhancer factorDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serum1The abbreviations used are: AP-1activating protein-1TRE12-O-tetradecanoylphorbol-13-acetate response elementMRFmyogenic regulatory factorMEFmyocyte enhancer factorDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serum transcription complex is intrinsically involved in diverse cellular processes such as transformation, apoptosis, proliferation, and differentiation (1.Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3249) Google Scholar). The diverse cellular responses to AP-1 activity may, in part, be mediated by the specific subunit composition of the AP-1 complex. This complex is a dimer of the Jun and Fos proto-oncogene families that binds to acis element termed the TRE (12-O-tetradecanoylphorbol-13-acetate response element) with the consensus 5′-TGAC/GTCA-3′ (1.Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3249) Google Scholar). AP-1 is thus formed by a dimeric association between Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra-1, and Fra-2) family proteins or a subset of ATF proteins. Therefore, a primary issue in understanding AP-1 activity concerns the functional properties of the different AP-1 dimer combinations. For example, in mouse fibroblasts JunD has an antiproliferative role, whereas c-Jun promotes S-phase entry and proliferation (2.Pfarr C.M. Mechta F. Spyrou G. Lallemand D. Carillo S. Yaniv M. Cell. 1994; 76: 747-760Abstract Full Text PDF PubMed Scopus (285) Google Scholar, 3.Kovary K. Bravo R. Mol. Cell. Biol. 1992; 12: 5015-5023Crossref PubMed Scopus (181) Google Scholar). Furthermore, the role of AP-1 in apoptosis is complex, dependent on the cellular context, and while c-Jun appears to be pro-apoptotic, JunD protects cells from senescence and apoptosis (4.Bossy-Wetzel E. Bakiri L. Yaniv M. EMBO J. 1997; 16: 1695-1709Crossref PubMed Scopus (377) Google Scholar). Since AP-1 components are differentially expressed during development and in different tissues, it is likely that heterogeneous AP-1 complexes fulfill distinct roles in cells of different lineage. This idea is supported by gene targeting experiments in which c-Fos −/− mice have impaired bone development but are viable (5.Grigoriadis A.E. Wang Z.Q. Cecchini M.G. Hofstetter W. Felix R. Fleisch H.A. Wagner E.F. Science. 1994; 266: 443-448Crossref PubMed Scopus (1061) Google Scholar), c-jun and junB knock-outs are lethal (6.Hilberg F. Aguzzi A. Howells N. Wagner E.F. Nature. 1993; 365: 179-181Crossref PubMed Scopus (461) Google Scholar, 7.Johnson R.S. van Lingen B. Papaioannou V.E. Spiegelman B.M. Genes Dev. 1993; 7: 1309-1317Crossref PubMed Scopus (343) Google Scholar, 8.Schorpp-Kistner M. Wang Z.Q. Angel P. Wagner E.F. EMBO J. 1999; 18: 934-948Crossref PubMed Scopus (213) Google Scholar) and targeted disruption of the junD gene results in specific defects in male reproductive function (9.Thepot D. Weitzman J.B. Barra J. Segretain D. Stinnakre M.-G. Babinet C. Yaniv M. Development (Camb.). 2000; 127: 143-153Crossref PubMed Google Scholar). The importance of AP-1 composition for specific biological responses is also exemplified in cellular transformation of NIH 3T3 by Ras; JunD is down-regulated in contrast to c-Jun levels, which increase. Overexpression of JunD also antagonizes transformation. The Jun proteins are responsive to an array of stimuli such as UV irradiation, cytokines, oxidative stress, and growth factors (1.Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3249) Google Scholar, 10.Angel P. Hattori K. Smeal T. Karin M. Cell. 1988; 55: 875-885Abstract Full Text PDF PubMed Scopus (986) Google Scholar, 11.Derijard B. Hibi M. Wu I.-H. Barrett T. Su B. Deng T. Karin M. Davis R. Cell. 1994; 76: 1025-1037Abstract Full Text PDF PubMed Scopus (2949) Google Scholar, 12.Devary Y. Gottlieb R.A. Lau L.F. Karin M. Mol. Cell. Biol. 1991; 11: 2804-2811Crossref PubMed Scopus (597) Google Scholar, 13.Hibi M. Lin A. Smeal T. Minden A. Karin M. Genes Dev. 1993; 7: 2135-2148Crossref PubMed Scopus (1705) Google Scholar). At least some of these signals are mediated by activation of the JNK/SAPK kinase cascade (13.Hibi M. Lin A. Smeal T. Minden A. Karin M. Genes Dev. 1993; 7: 2135-2148Crossref PubMed Scopus (1705) Google Scholar, 14.Karin M. J. Biol. Chem. 1995; 270: 16483-16486Abstract Full Text Full Text PDF PubMed Scopus (2245) Google Scholar, 15.Karin M. Liu Z. Zandi E. Curr. Opin. Cell Biol. 1997; 9: 240-246Crossref PubMed Scopus (2281) Google Scholar, 16.Kyriakis J.M. Banerjee P. Nikolakaki E. Dai T. Rubie E.A. Ahmad M.F. Avruch J. Woodgett J.R. Nature. 1994; 369: 156-160Crossref PubMed Scopus (2408) Google Scholar). Thus, the specific AP-1 dimer composition and also the targeting of these components by cellular signaling pathways provide the cell with complex machinery to modulate genes bearing this TRE element. Additional studies to clarify the function of specific AP-1 dimers in different cell types are therefore paramount to understanding the biology of AP-1 function in vivo, both during development and also in the adult.The process of muscle differentiation has proved to be a powerful model for studying mechanisms of tissue-specific transcriptional control (17.Davis R.L. Weintraub H. Lassar A.B. Cell. 1987; 51: 987-1000Abstract Full Text PDF PubMed Scopus (2440) Google Scholar,18.Molkentin J.D. Black B.L. Martin J.F. Olson E.N. Cell. 1995; 83: 1125-1136Abstract Full Text PDF PubMed Scopus (698) Google Scholar). The identification and extensive characterization of the basic helix-loop-helix myogenic regulatory factors (MRFs) and the myocyte enhancer factor 2 (MEF2) transcription factors have led to the establishment of a paradigm for the regulation of tissue specific gene expression (17.Davis R.L. Weintraub H. Lassar A.B. Cell. 1987; 51: 987-1000Abstract Full Text PDF PubMed Scopus (2440) Google Scholar, 18.Molkentin J.D. Black B.L. Martin J.F. Olson E.N. Cell. 1995; 83: 1125-1136Abstract Full Text PDF PubMed Scopus (698) Google Scholar). In contrast, the physiological role for AP-1 during myogenesis is not well defined. Initial studies showed that c-Jun represses myogenesis due to a direct physical antagonism of the activity of the MRF family members, MyoD and myogenin (19.Li L. Chambard J. Karin M. Olson E.N. Genes Dev. 1992; 6: 676-689Crossref PubMed Scopus (186) Google Scholar, 20.Bengal E. Ransone L. Scharfmann R. Dwarki V.J. Tapscott S.J. Weintraub H. Verma I.M. Cell. 1992; 68: 507-519Abstract Full Text PDF PubMed Scopus (323) Google Scholar, 21.Grossi M. Calconi A. Tato F. Oncogene. 1991; 6: 1767-1773PubMed Google Scholar). However, one hallmark of these studies was that the effects on myogenesis were dependent on high levels of c-Jun overexpression from retroviral vectors, possibly implying that the mechanism of inhibition was through competition with the MRFs for a limiting factor such as CBP/p300. Moreover, mice expressing an H-2K-v-Jun transgene develop malignant sarcomas that contain focal areas of skeletal muscle (22.Scuh A.C. Keating S.J. Yeung M.C. Breitman M.L. Oncogene. 1992; 7: 667-676PubMed Google Scholar). These observations are consistent with the idea that expression of v-Jun in transgenic tumors is compatible with skeletal muscle differentiation.Since these studies, the full complexity of AP-1 has been documented, and it is possible that c-Jun overexpression in these earlier investigations disturbed the requirement for precise balance of AP-1 components in the cells. This idea is supported by observations that AP-1 components can be detected in differentiating myogenic cells, and some of the MRF gene promoters and certain muscle structural genes contain TRE elements. Thus, co-expression of AP-1 proteins with myogenic and structural proteins is compatible with a positive role for physiological levels of AP-1 in myogenic differentiation (23.Aurade F. Pfarr C.M. Lindon C. Garcia A. Primig M. Montarras D. Pinset C. J. Cell Sci. 1997; 110: 2771-2779PubMed Google Scholar, 24.Thinakaran G. Bag J. Biochem. Cell Biol. 1993; 71: 260-269Crossref PubMed Scopus (3) Google Scholar, 25.Thinakaran G. Ojaia J. Bag J. FEBS. 1993; 319: 271-276Crossref PubMed Scopus (24) Google Scholar, 26.Bishopric N.H. Jayasena V. Webster K.A. J. Biol. Chem. 1992; 267: 25535-25540Abstract Full Text PDF PubMed Google Scholar, 27.Kucharczuk K.L. Love C.M. Dougherty N.M. Goldhamer D.J. Development (Camb.). 1999; 126: 1957-1965PubMed Google Scholar, 28.Dorman C.M. Johnson S.E. J. Biol. Chem. 2000; 275: 27481-27487Abstract Full Text Full Text PDF PubMed Google Scholar).Here, we report that the subunit structure of the AP-1 complex undergoes a transition from a “proliferation”- to “differentiation”-specific, Fra-2-containing complex during myogenesis. Also, the transcriptional control of the c-jungene promoter becomes partially under the control of muscle specific transcription complexes during differentiation. These data highlight the complex role of heterogeneous AP-1 complexes in the context of muscle cell differentiation.DISCUSSIONHere we present data pertaining to the expression and activity of AP-1 in myogenic cells. AP-1 activity in differentiating muscle cells raises the possibility, contrary to previous ideas, that it may play a positive role during myogenesis. Since the AP-1 complex in proliferating myoblasts is distinct from that of terminally differentiated myotubes, differentiation-specific changes in AP-1 composition may reflect dynamic changes in the activation of AP-1 target genes in these cells. In differentiating muscle cells the predominant AP-1 complex consists of a heterodimer comprised of Fra-2 complexed with c-Jun or JunD. The increased level of Fra-2 in the myotube AP-1 complex is correlated with cell cycle withdrawal and the activation of muscle gene expression. Thus, these data suggest that a different set of AP-1 target genes may be activated by heterogeneous AP-1 complexes during differentiation. It is likely that there are a multitude of AP-1 target genes in muscle, but one notable target could be MRF family members. Here we show that Fra-2-containing AP-1 complexes can transactivate the MyoD core enhancer. Although the functional implications of changes in the AP-1 subunit composition are incompletely understood at this point, it is clear that the AP-1 complex in differentiating muscle cells is distinct from that in proliferating myoblasts.An important level of regulation of AP-1 occurs through controlling its activity and concentration within the cell (1.Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3249) Google Scholar). For example the activity of c-Jun and Fra-2 is regulated through phosphorylation (14.Karin M. J. Biol. Chem. 1995; 270: 16483-16486Abstract Full Text Full Text PDF PubMed Scopus (2245) Google Scholar,36.Musti A.M. Treier M. Bohmann D. Cell. 1997; 275: 400-402Google Scholar, 37.Murukami M. Sonobe M.H. Ui M. Kabuyama Y. Atanabe H. Takahashi A. Han H. Iba H.E. Oncogene. 1997; 14: 2435-2444Crossref PubMed Scopus (55) Google Scholar). In response to various stressors such as UV, heat, or TNF-α, c-Jun is phosphorylated on Ser63 and, more prominently, Ser73 in its activation domain by the JNKs (14.Karin M. J. Biol. Chem. 1995; 270: 16483-16486Abstract Full Text Full Text PDF PubMed Scopus (2245) Google Scholar, 16.Kyriakis J.M. Banerjee P. Nikolakaki E. Dai T. Rubie E.A. Ahmad M.F. Avruch J. Woodgett J.R. Nature. 1994; 369: 156-160Crossref PubMed Scopus (2408) Google Scholar). This phosphorylated c-Jun can then interact with co-activators CBP/p300 to increase transactivation of target genes. The abundance of c-Jun is also regulated at the level of protein stability. The half-life of c-Jun is ∼90 min, and degradation of c-Jun has been shown to be mediated by the ubiquitin pathway (36.Musti A.M. Treier M. Bohmann D. Cell. 1997; 275: 400-402Google Scholar). However, phosphorylation of c-Jun by the JNKs decreases c-Jun ubiquitination and increases its stability (36.Musti A.M. Treier M. Bohmann D. Cell. 1997; 275: 400-402Google Scholar). Less is known concerning the regulation of Fra-2 by phosphorylation, but the present study indicates that both JunD and Fra-2 are modified by phosphorylation in myogenic cells. The implications of this post-translational regulation of Fra-2 and JunD during myogenesis is thus of considerable interest.Activation of c-jun transcription through the c-jun enhancer/promoter is elevated in growing HeLa cells. We attribute this to the various sites in the enhancer, i.e. NF-jun, jun1, jun2, SP1, and the CAAT box, which are bound by various transcription factor complexes. However, endogenous MEF2 proteins in HeLa do not contribute to this activation, since the c-jun enhancer, which contains a mutated MEF2 binding site, has the same activity as the wild type enhancer when it is transfected. Therefore in HeLa cells, the basal levels of c-jun transcription do not depend on the MEF2 site. In contrast to the minimal role played in proliferating cells, we show that the MEF2 site in the c-jun enhancer is an important regulatory element in myogenic cells, since a mutated MEF2 site in the c-jun enhancer leads to a considerable diminution of reporter activity during differentiation. The residual enhancer activity remaining when the MEF2 site is mutated is due to the contribution from the other transcription factor binding sites or possibly as yet unknown cis elements in the c-junenhancer.Previous studies have suggested that a putative AP-1/CRE element at −342 to −322 of the MyoD promoter is a negative regulator of MyoD expression (38.Pedraza Alva G. Zingg J.-M. Jost J.-P. J. Biol. Chem. 1994; 269: 6978-6985Abstract Full Text PDF PubMed Google Scholar). This element is not a classical AP-1 site but fits the consensus as a cAMP-responsive element. Previous studies suggest the involvement of AP-1 in the regulation of this element. However, even though c-Jun and c-Fos were implicated in negative control of the MyoD promoter through this element, it is not yet known what the role of a different AP-1 dimer combination could be. Our initial studies with overexpression of Fra-2 indicate that it can activate the 2.5-kb MyoD promoter containing this element, thus supporting the notion that there could be differential regulation through this element depending on the specific AP-1 dimer binding there. Additional studies of the MyoD gene have indicated the presence of a consensus AP-1 site in the middle of a region referred to as the MyoD core enhancer, which is located 20 kb away from the transcriptional start site (27.Kucharczuk K.L. Love C.M. Dougherty N.M. Goldhamer D.J. Development (Camb.). 1999; 126: 1957-1965PubMed Google Scholar). Thus, further studies dissecting the role of AP-1 dimer combinations on the MyoD promoter may be important in determining the control of MyoD expression.Considering our data, along with those of others, we propose a testable model (Fig. 6) for the inclusion of specific AP-1 complexes in a sub-circuit of the myogenic regulatory hierarchy. In this model we propose that MEF2, which is strongly induced during myogenic differentiation, activates c-Jun expression. JunD/c-Jun dimerize with Fra-2 that becomes a major component of the AP-1 complex in differentiating cells. Since Fra-2 is expressed throughout the time course of differentiation, this change in Fra-2's contribution to the AP-1 complex likely reflects post-translational control of its DNA binding properties. Fra-2-containing AP-1 complexes can then target muscle genes and also contribute to the transcriptional activation of the MRFs. The MRFs are known to be able to induce MEF2 activity; and in the current study, we also present data suggesting that one of the MRFs, MyoD, can affect the transcription of c-jun through the MEF2 element, thus completing a self-reinforcing feedback circuit. This model is based on data from the current study and those of others (18.Molkentin J.D. Black B.L. Martin J.F. Olson E.N. Cell. 1995; 83: 1125-1136Abstract Full Text PDF PubMed Scopus (698) Google Scholar, 23.Aurade F. Pfarr C.M. Lindon C. Garcia A. Primig M. Montarras D. Pinset C. J. Cell Sci. 1997; 110: 2771-2779PubMed Google Scholar, 24.Thinakaran G. Bag J. Biochem. Cell Biol. 1993; 71: 260-269Crossref PubMed Scopus (3) Google Scholar, 28.Dorman C.M. Johnson S.E. J. Biol. Chem. 2000; 275: 27481-27487Abstract Full Text Full Text PDF PubMed Google Scholar, 30.Ornatsky O.I. Andreucci J.J. McDermott J.C. J. Biol. Chem. 1997; 272: 33271-33278Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 32.Lamph W.W. Wamsley P. Sassone-Corsi P. Verma I.M. Nature. 1988; 334: 629-631Crossref PubMed Scopus (502) Google Scholar, 33.Han T. Prywes R. Mol. Cell. Biol. 1995; 15: 2907-2915Crossref PubMed Scopus (167) Google Scholar).Several studies in the early nineties suggested that AP-1 is inhibitory for myogenesis because of the observation that overexpression of c-Jun inhibits myogenesis due to a direct physical antagonism between the leucine zipper of c-Jun and the helix-loop-helix domain of MyoD (19.Li L. Chambard J. Karin M. Olson E.N. Genes Dev. 1992; 6: 676-689Crossref PubMed Scopus (186) Google Scholar, 20.Bengal E. Ransone L. Scharfmann R. Dwarki V.J. Tapscott S.J. Weintraub H. Verma I.M. Cell. 1992; 68: 507-519Abstract Full Text PDF PubMed Scopus (323) Google Scholar, 41.Su H. Bos T.J. Montecarlo F.S. Vogt P.K. Oncogene. 1991; 6: 1759-1766PubMed Google Scholar). While the physical basis for the antagonism between the two proteins when overexpressed is correct, based on our current data, we contend that these observations have masked the role of endogenous AP-1 in myogenic cells. A role for specific AP-1 complexes is not without precedent having been implicated in cellular differentiation in ovarian granulosa cells and osteoblasts (39.Sharma S.C. Richards J.S. J. Biol. Chem. 2000; 275: 33718-33728Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 40.McCabe L.R. Banerjee C. Kundu R. Harrison R.J. Dobner P.R. Stein J.L. Lian J.B. Stein G.S. Endocrinology. 1996; 137: 4398-4408Crossref PubMed Scopus (161) Google Scholar). The pleiotropic and often contradictory functional role of AP-1 raises the question of how can AP-1 mediate such contrasting processes? One possible explanation, based on evidence presented by others and ourselves, is that changes in the composition or phosphorylation of AP-1 subunits can modulate its activity such that its target genes and biological function are dynamically altered. We therefore propose that physiological levels of an AP-1 complex consisting of a JunD/Fra-2 or a c-Jun/Fra-2 heterodimer is consistent with, and not antagonistic to, myogenic differentiation. We also show data indicating that AP-1 may play a role in the full activation of MyoD expression due to direct effects on the MyoD promoter. These data implicate specific AP-1 subunits in the positive control of muscle differentiation. The activating protein-1 (AP-1) 1The abbreviations used are: AP-1activating protein-1TRE12-O-tetradecanoylphorbol-13-acetate response elementMRFmyogenic regulatory factorMEFmyocyte enhancer factorDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serum1The abbreviations used are: AP-1activating protein-1TRE12-O-tetradecanoylphorbol-13-acetate response elementMRFmyogenic regulatory factorMEFmyocyte enhancer factorDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serum transcription complex is intrinsically involved in diverse cellular processes such as transformation, apoptosis, proliferation, and differentiation (1.Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3249) Google Scholar). The diverse cellular responses to AP-1 activity may, in part, be mediated by the specific subunit composition of the AP-1 complex. This complex is a dimer of the Jun and Fos proto-oncogene families that binds to acis element termed the TRE (12-O-tetradecanoylphorbol-13-acetate response element) with the consensus 5′-TGAC/GTCA-3′ (1.Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3249) Google Scholar). AP-1 is thus formed by a dimeric association between Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra-1, and Fra-2) family proteins or a subset of ATF proteins. Therefore, a primary issue in understanding AP-1 activity concerns the functional properties of the different AP-1 dimer combinations. For example, in mouse fibroblasts JunD has an antiproliferative role, whereas c-Jun promotes S-phase entry and proliferation (2.Pfarr C.M. Mechta F. Spyrou G. Lallemand D. Carillo S. Yaniv M. Cell. 1994; 76: 747-760Abstract Full Text PDF PubMed Scopus (285) Google Scholar, 3.Kovary K. Bravo R. Mol. Cell. Biol. 1992; 12: 5015-5023Crossref PubMed Scopus (181) Google Scholar). Furthermore, the role of AP-1 in apoptosis is complex, dependent on the cellular context, and while c-Jun appears to be pro-apoptotic, JunD protects cells from senescence and apoptosis (4.Bossy-Wetzel E. Bakiri L. Yaniv M. EMBO J. 1997; 16: 1695-1709Crossref PubMed Scopus (377) Google Scholar). Since AP-1 components are differentially expressed during development and in different tissues, it is likely that heterogeneous AP-1 complexes fulfill distinct roles in cells of different lineage. This idea is supported by gene targeting experiments in which c-Fos −/− mice have impaired bone development but are viable (5.Grigoriadis A.E. Wang Z.Q. Cecchini M.G. Hofstetter W. Felix R. Fleisch H.A. Wagner E.F. Science. 1994; 266: 443-448Crossref PubMed Scopus (1061) Google Scholar), c-jun and junB knock-outs are lethal (6.Hilberg F. Aguzzi A. Howells N. Wagner E.F. Nature. 1993; 365: 179-181Crossref PubMed Scopus (461) Google Scholar, 7.Johnson R.S. van Lingen B. Papaioannou V.E. Spiegelman B.M. Genes Dev. 1993; 7: 1309-1317Crossref PubMed Scopus (343) Google Scholar, 8.Schorpp-Kistner M. Wang Z.Q. Angel P. Wagner E.F. EMBO J. 1999; 18: 934-948Crossref PubMed Scopus (213) Google Scholar) and targeted disruption of the junD gene results in specific defects in male reproductive function (9.Thepot D. Weitzman J.B. Barra J. Segretain D. Stinnakre M.-G. Babinet C. Yaniv M. Development (Camb.). 2000; 127: 143-153Crossref PubMed Google Scholar). The importance of AP-1 composition for specific biological responses is also exemplified in cellular transformation of NIH 3T3 by Ras; JunD is down-regulated in contrast to c-Jun levels, which increase. Overexpression of JunD also antagonizes transformation. The Jun proteins are responsive to an array of stimuli such as UV irradiation, cytokines, oxidative stress, and growth factors (1.Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3249) Google Scholar, 10.Angel P. Hattori K. Smeal T. Karin M. Cell. 1988; 55: 875-885Abstract Full Text PDF PubMed Scopus (986) Google Scholar, 11.Derijard B. Hibi M. Wu I.-H. Barrett T. Su B. Deng T. Karin M. Davis R. Cell. 1994; 76: 1025-1037Abstract Full Text PDF PubMed Scopus (2949) Google Scholar, 12.Devary Y. Gottlieb R.A. Lau L.F. Karin M. Mol. Cell. Biol. 1991; 11: 2804-2811Crossref PubMed Scopus (597) Google Scholar, 13.Hibi M. Lin A. Smeal T. Minden A. Karin M. Genes Dev. 1993; 7: 2135-2148Crossref PubMed Scopus (1705) Google Scholar). At least some of these signals are mediated by activation of the JNK/SAPK kinase cascade (13.Hibi M. Lin A. Smeal T. Minden A. Karin M. Genes Dev. 1993; 7: 2135-2148Crossref PubMed Scopus (1705) Google Scholar, 14.Karin M. J. Biol. Chem. 1995; 270: 16483-16486Abstract Full Text Full Text PDF PubMed Scopus (2245) Google Scholar, 15.Karin M. Liu Z. Zandi E. Curr. Opin. Cell Biol. 1997; 9: 240-246Crossref PubMed Scopus (2281) Google Scholar, 16.Kyriakis J.M. Banerjee P. Nikolakaki E. Dai T. Rubie E.A. Ahmad M.F. Avruch J. Woodgett J.R. Nature. 1994; 369: 156-160Crossref PubMed Scopus (2408) Google Scholar). Thus, the specific AP-1 dimer composition and also the targeting of these components by cellular signaling pathways provide the cell with complex machinery to modulate genes bearing this TRE element. Additional studies to clarify the function of specific AP-1 dimers in different cell types are therefore paramount to understanding the biology of AP-1 function in vivo, both during development and also in the adult. activating protein-1 12-O-tetradecanoylphorbol-13-acetate response element myogenic regulatory factor myocyte enhancer factor Dulbecco's modified Eagle's medium fetal bovine serum activating protein-1 12-O-tetradecanoylphorbol-13-acetate response element myogenic regulatory factor myocyte enhancer factor Dulbecco's modified Eagle's medium fetal bovine serum The process of muscle differentiation has proved to be a powerful model for studying mechanisms of tissue-specific transcriptional control (17.Davis R.L. Weintraub H. Lassar A.B. Cell. 1987; 51: 987-1000Abstract Full Text PDF PubMed Scopus (2440) Google Scholar,18.Molkentin J.D. Black B.L. Martin J.F. Olson E.N. Cell. 1995; 83: 1125-1136Abstract Full Text PDF PubMed Scopus (698) Google Scholar). The identification and extensive characterization of the basic helix-loop-helix myogenic regulatory factors (MRFs) and the myocyte enhancer factor 2 (MEF2) transcription factors have led to the establishment of a paradigm for the regulation of tissue specific gene expression (17.Davis R.L. Weintraub H. Lassar A.B. Cell. 1987; 51: 987-1000Abstract Full Text PDF PubMed Scopus (2440) Google Scholar, 18.Molkentin J.D. Black B.L. Martin J.F. Olson E.N. Cell. 1995; 83: 1125-1136Abstract Full Text PDF PubMed Scopus (698) Google Scholar). In contrast, the physiological role for AP-1 during myogenesis is not well defined. Initial studies showed that c-Jun represses myogenesis due to a direct physical antagonism of the activity of the MRF family members, MyoD and myogenin (19.Li L. Chambard J. Karin M. Olson E.N. Genes Dev. 1992; 6: 676-689Crossref PubMed Scopus (186) Google Scholar, 20.Bengal E. Ransone L. Scharfmann R. Dwarki V.J. Tapscott S.J. Weintraub H. Verma I.M. Cell. 1992; 68: 507-519Abstract Full Text PDF PubMed Scopus (323) Google Scholar, 21.Grossi M. Calconi A. Tato F. Oncogene. 1991; 6: 1767-1773PubMed Google Scholar). However, one hallmark of these studies was that the effects on myogenesis were dependent on high levels of c-Jun overexpression from retroviral vectors, possibly implying that the mechanism of inhibition was through competition with the MRFs for a limiting factor such as CBP/p300. Moreover, mice expressing an H-2K-v-Jun transgene develop malignant sarcomas that contain focal areas of skeletal muscle (22.Scuh A.C. Keating S.J. Yeung M.C. Breitman M.L. Oncogene. 1992; 7: 667-676PubMed Google Scholar). These observations are consistent with the idea that expression of v-Jun in transgenic tumors is compatible with skeletal muscle differentiation. Since these studies, the full complexity of AP-1 has been documented, and it is possible that c-Jun overexpression in these earlier investigations disturbed the requirement for precise balance of AP-1 components in the cells. This idea is supported by observations that AP-1 components can be detected in differentiating myogenic cells, and some of the MRF gene promoters and certain muscle structural genes contain TRE elements. Thus, co-expression of AP-1 proteins with myogenic and structural proteins is compatible with a positive role for physiological levels of AP-1 in myogenic differentiation (23.Aurade F. Pfarr C.M. Lindon C. Garcia A. Primig M. Montarras D. Pinset C. J. Cell Sci. 1997; 110: 2771-2779PubMed Google Scholar, 24.Thinakaran G. Bag J. Biochem. Cell Biol. 1993; 71: 260-269Crossref PubMed Scopus (3) Google Scholar, 25.Thinakaran G. Ojaia J. Bag J. FEBS. 1993; 319: 271-276Crossref PubMed Scopus (24) Google Scholar, 26.Bishopric N.H. Jayasena V. Webster K.A. J. Biol. Chem. 1992; 267: 25535-25540Abstract Full Text PDF PubMed Google Scholar, 27.Kucharczuk K.L. Love C.M. Dougherty N.M. Goldhamer D.J. Development (Camb.). 1999; 126: 1957-1965PubMed Google Scholar, 28.Dorman C.M. Johnson S.E. J. Biol. Chem. 2000; 275: 27481-27487Abstract Full Text Full Text PDF PubMed Google Scholar). Here, we report that the subunit structure of the AP-1 complex undergoes a transition from a “proliferation”- to “differentiation”-specific, Fra-2-containing complex during myogenesis. Also, the transcriptional control of the c-jungene promoter becomes partially under the control of muscle specific transcription complexes during differentiation. These data highlight the complex role of heterogeneous AP-1 complexes in the context of muscle cell differentiation. DISCUSSIONHere we present data pertaining to the expression and activity of AP-1 in myogenic cells. AP-1 activity in differentiating muscle cells raises the possibility, contrary to previous ideas, that it may play a positive role during myogenesis. Since the AP-1 complex in proliferating myoblasts is distinct from that of terminally differentiated myotubes, differentiation-specific changes in AP-1 composition may reflect dynamic changes in the activation of AP-1 target genes in these cells. In differentiating muscle cells the predominant AP-1 complex consists of a heterodimer comprised of Fra-2 complexed with c-Jun or JunD. The increased level of Fra-2 in the myotube AP-1 complex is correlated with cell cycle withdrawal and the activation of muscle gene expression. Thus, these data suggest that a different set of AP-1 target genes may be activated by heterogeneous AP-1 complexes during differentiation. It is likely that there are a multitude of AP-1 target genes in muscle, but one notable target could be MRF family members. Here we show that Fra-2-containing AP-1 complexes can transactivate the MyoD core enhancer. Although the functional implications of changes in the AP-1 subunit composition are incompletely understood at this point, it is clear that the AP-1 complex in differentiating muscle cells is distinct from that in proliferating myoblasts.An important level of regulation of AP-1 occurs through controlling its activity and concentration within the cell (1.Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3249) Google Scholar). For example the activity of c-Jun and Fra-2 is regulated through phosphorylation (14.Karin M. J. Biol. Chem. 1995; 270: 16483-16486Abstract Full Text Full Text PDF PubMed Scopus (2245) Google Scholar,36.Musti A.M. Treier M. Bohmann D. Cell. 1997; 275: 400-402Google Scholar, 37.Murukami M. Sonobe M.H. Ui M. Kabuyama Y. Atanabe H. Takahashi A. Han H. Iba H.E. Oncogene. 1997; 14: 2435-2444Crossref PubMed Scopus (55) Google Scholar). In response to various stressors such as UV, heat, or TNF-α, c-Jun is phosphorylated on Ser63 and, more prominently, Ser73 in its activation domain by the JNKs (14.Karin M. J. Biol. Chem. 1995; 270: 16483-16486Abstract Full Text Full Text PDF PubMed Scopus (2245) Google Scholar, 16.Kyriakis J.M. Banerjee P. Nikolakaki E. Dai T. Rubie E.A. Ahmad M.F. Avruch J. Woodgett J.R. Nature. 1994; 369: 156-160Crossref PubMed Scopus (2408) Google Scholar). This phosphorylated c-Jun can then interact with co-activators CBP/p300 to increase transactivation of target genes. The abundance of c-Jun is also regulated at the level of protein stability. The half-life of c-Jun is ∼90 min, and degradation of c-Jun has been shown to be mediated by the ubiquitin pathway (36.Musti A.M. Treier M. Bohmann D. Cell. 1997; 275: 400-402Google Scholar). However, phosphorylation of c-Jun by the JNKs decreases c-Jun ubiquitination and increases its stability (36.Musti A.M. Treier M. Bohmann D. Cell. 1997; 275: 400-402Google Scholar). Less is known concerning the regulation of Fra-2 by phosphorylation, but the present study indicates that both JunD and Fra-2 are modified by phosphorylation in myogenic cells. The implications of this post-translational regulation of Fra-2 and JunD during myogenesis is thus of considerable interest.Activation of c-jun transcription through the c-jun enhancer/promoter is elevated in growing HeLa cells. We attribute this to the various sites in the enhancer, i.e. NF-jun, jun1, jun2, SP1, and the CAAT box, which are bound by various transcription factor complexes. However, endogenous MEF2 proteins in HeLa do not contribute to this activation, since the c-jun enhancer, which contains a mutated MEF2 binding site, has the same activity as the wild type enhancer when it is transfected. Therefore in HeLa cells, the basal levels of c-jun transcription do not depend on the MEF2 site. In contrast to the minimal role played in proliferating cells, we show that the MEF2 site in the c-jun enhancer is an important regulatory element in myogenic cells, since a mutated MEF2 site in the c-jun enhancer leads to a considerable diminution of reporter activity during differentiation. The residual enhancer activity remaining when the MEF2 site is mutated is due to the contribution from the other transcription factor binding sites or possibly as yet unknown cis elements in the c-junenhancer.Previous studies have suggested that a putative AP-1/CRE element at −342 to −322 of the MyoD promoter is a negative regulator of MyoD expression (38.Pedraza Alva G. Zingg J.-M. Jost J.-P. J. Biol. Chem. 1994; 269: 6978-6985Abstract Full Text PDF PubMed Google Scholar). This element is not a classical AP-1 site but fits the consensus as a cAMP-responsive element. Previous studies suggest the involvement of AP-1 in the regulation of this element. However, even though c-Jun and c-Fos were implicated in negative control of the MyoD promoter through this element, it is not yet known what the role of a different AP-1 dimer combination could be. Our initial studies with overexpression of Fra-2 indicate that it can activate the 2.5-kb MyoD promoter containing this element, thus supporting the notion that there could be differential regulation through this element depending on the specific AP-1 dimer binding there. Additional studies of the MyoD gene have indicated the presence of a consensus AP-1 site in the middle of a region referred to as the MyoD core enhancer, which is located 20 kb away from the transcriptional start site (27.Kucharczuk K.L. Love C.M. Dougherty N.M. Goldhamer D.J. Development (Camb.). 1999; 126: 1957-1965PubMed Google Scholar). Thus, further studies dissecting the role of AP-1 dimer combinations on the MyoD promoter may be important in determining the control of MyoD expression.Considering our data, along with those of others, we propose a testable model (Fig. 6) for the inclusion of specific AP-1 complexes in a sub-circuit of the myogenic regulatory hierarchy. In this model we propose that MEF2, which is strongly induced during myogenic differentiation, activates c-Jun expression. JunD/c-Jun dimerize with Fra-2 that becomes a major component of the AP-1 complex in differentiating cells. Since Fra-2 is expressed throughout the time course of differentiation, this change in Fra-2's contribution to the AP-1 complex likely reflects post-translational control of its DNA binding properties. Fra-2-containing AP-1 complexes can then target muscle genes and also contribute to the transcriptional activation of the MRFs. The MRFs are known to be able to induce MEF2 activity; and in the current study, we also present data suggesting that one of the MRFs, MyoD, can affect the transcription of c-jun through the MEF2 element, thus completing a self-reinforcing feedback circuit. This model is based on data from the current study and those of others (18.Molkentin J.D. Black B.L. Martin J.F. Olson E.N. Cell. 1995; 83: 1125-1136Abstract Full Text PDF PubMed Scopus (698) Google Scholar, 23.Aurade F. Pfarr C.M. Lindon C. Garcia A. Primig M. Montarras D. Pinset C. J. Cell Sci. 1997; 110: 2771-2779PubMed Google Scholar, 24.Thinakaran G. Bag J. Biochem. Cell Biol. 1993; 71: 260-269Crossref PubMed Scopus (3) Google Scholar, 28.Dorman C.M. Johnson S.E. J. Biol. Chem. 2000; 275: 27481-27487Abstract Full Text Full Text PDF PubMed Google Scholar, 30.Ornatsky O.I. Andreucci J.J. McDermott J.C. J. Biol. Chem. 1997; 272: 33271-33278Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 32.Lamph W.W. Wamsley P. Sassone-Corsi P. Verma I.M. Nature. 1988; 334: 629-631Crossref PubMed Scopus (502) Google Scholar, 33.Han T. Prywes R. Mol. Cell. Biol. 1995; 15: 2907-2915Crossref PubMed Scopus (167) Google Scholar).Several studies in the early nineties suggested that AP-1 is inhibitory for myogenesis because of the observation that overexpression of c-Jun inhibits myogenesis due to a direct physical antagonism between the leucine zipper of c-Jun and the helix-loop-helix domain of MyoD (19.Li L. Chambard J. Karin M. Olson E.N. Genes Dev. 1992; 6: 676-689Crossref PubMed Scopus (186) Google Scholar, 20.Bengal E. Ransone L. Scharfmann R. Dwarki V.J. Tapscott S.J. Weintraub H. Verma I.M. Cell. 1992; 68: 507-519Abstract Full Text PDF PubMed Scopus (323) Google Scholar, 41.Su H. Bos T.J. Montecarlo F.S. Vogt P.K. Oncogene. 1991; 6: 1759-1766PubMed Google Scholar). While the physical basis for the antagonism between the two proteins when overexpressed is correct, based on our current data, we contend that these observations have masked the role of endogenous AP-1 in myogenic cells. A role for specific AP-1 complexes is not without precedent having been implicated in cellular differentiation in ovarian granulosa cells and osteoblasts (39.Sharma S.C. Richards J.S. J. Biol. Chem. 2000; 275: 33718-33728Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 40.McCabe L.R. Banerjee C. Kundu R. Harrison R.J. Dobner P.R. Stein J.L. Lian J.B. Stein G.S. Endocrinology. 1996; 137: 4398-4408Crossref PubMed Scopus (161) Google Scholar). The pleiotropic and often contradictory functional role of AP-1 raises the question of how can AP-1 mediate such contrasting processes? One possible explanation, based on evidence presented by others and ourselves, is that changes in the composition or phosphorylation of AP-1 subunits can modulate its activity such that its target genes and biological function are dynamically altered. We therefore propose that physiological levels of an AP-1 complex consisting of a JunD/Fra-2 or a c-Jun/Fra-2 heterodimer is consistent with, and not antagonistic to, myogenic differentiation. We also show data indicating that AP-1 may play a role in the full activation of MyoD expression due to direct effects on the MyoD promoter. These data implicate specific AP-1 subunits in the positive control of muscle differentiation. Here we present data pertaining to the expression and activity of AP-1 in myogenic cells. AP-1 activity in differentiating muscle cells raises the possibility, contrary to previous ideas, that it may play a positive role during myogenesis. Since the AP-1 complex in proliferating myoblasts is distinct from that of terminally differentiated myotubes, differentiation-specific changes in AP-1 composition may reflect dynamic changes in the activation of AP-1 target genes in these cells. In differentiating muscle cells the predominant AP-1 complex consists of a heterodimer comprised of Fra-2 complexed with c-Jun or JunD. The increased level of Fra-2 in the myotube AP-1 complex is correlated with cell cycle withdrawal and the activation of muscle gene expression. Thus, these data suggest that a different set of AP-1 target genes may be activated by heterogeneous AP-1 complexes during differentiation. It is likely that there are a multitude of AP-1 target genes in muscle, but one notable target could be MRF family members. Here we show that Fra-2-containing AP-1 complexes can transactivate the MyoD core enhancer. Although the functional implications of changes in the AP-1 subunit composition are incompletely understood at this point, it is clear that the AP-1 complex in differentiating muscle cells is distinct from that in proliferating myoblasts. An important level of regulation of AP-1 occurs through controlling its activity and concentration within the cell (1.Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3249) Google Scholar). For example the activity of c-Jun and Fra-2 is regulated through phosphorylation (14.Karin M. J. Biol. Chem. 1995; 270: 16483-16486Abstract Full Text Full Text PDF PubMed Scopus (2245) Google Scholar,36.Musti A.M. Treier M. Bohmann D. Cell. 1997; 275: 400-402Google Scholar, 37.Murukami M. Sonobe M.H. Ui M. Kabuyama Y. Atanabe H. Takahashi A. Han H. Iba H.E. Oncogene. 1997; 14: 2435-2444Crossref PubMed Scopus (55) Google Scholar). In response to various stressors such as UV, heat, or TNF-α, c-Jun is phosphorylated on Ser63 and, more prominently, Ser73 in its activation domain by the JNKs (14.Karin M. J. Biol. Chem. 1995; 270: 16483-16486Abstract Full Text Full Text PDF PubMed Scopus (2245) Google Scholar, 16.Kyriakis J.M. Banerjee P. Nikolakaki E. Dai T. Rubie E.A. Ahmad M.F. Avruch J. Woodgett J.R. Nature. 1994; 369: 156-160Crossref PubMed Scopus (2408) Google Scholar). This phosphorylated c-Jun can then interact with co-activators CBP/p300 to increase transactivation of target genes. The abundance of c-Jun is also regulated at the level of protein stability. The half-life of c-Jun is ∼90 min, and degradation of c-Jun has been shown to be mediated by the ubiquitin pathway (36.Musti A.M. Treier M. Bohmann D. Cell. 1997; 275: 400-402Google Scholar). However, phosphorylation of c-Jun by the JNKs decreases c-Jun ubiquitination and increases its stability (36.Musti A.M. Treier M. Bohmann D. Cell. 1997; 275: 400-402Google Scholar). Less is known concerning the regulation of Fra-2 by phosphorylation, but the present study indicates that both JunD and Fra-2 are modified by phosphorylation in myogenic cells. The implications of this post-translational regulation of Fra-2 and JunD during myogenesis is thus of considerable interest. Activation of c-jun transcription through the c-jun enhancer/promoter is elevated in growing HeLa cells. We attribute this to the various sites in the enhancer, i.e. NF-jun, jun1, jun2, SP1, and the CAAT box, which are bound by various transcription factor complexes. However, endogenous MEF2 proteins in HeLa do not contribute to this activation, since the c-jun enhancer, which contains a mutated MEF2 binding site, has the same activity as the wild type enhancer when it is transfected. Therefore in HeLa cells, the basal levels of c-jun transcription do not depend on the MEF2 site. In contrast to the minimal role played in proliferating cells, we show that the MEF2 site in the c-jun enhancer is an important regulatory element in myogenic cells, since a mutated MEF2 site in the c-jun enhancer leads to a considerable diminution of reporter activity during differentiation. The residual enhancer activity remaining when the MEF2 site is mutated is due to the contribution from the other transcription factor binding sites or possibly as yet unknown cis elements in the c-junenhancer. Previous studies have suggested that a putative AP-1/CRE element at −342 to −322 of the MyoD promoter is a negative regulator of MyoD expression (38.Pedraza Alva G. Zingg J.-M. Jost J.-P. J. Biol. Chem. 1994; 269: 6978-6985Abstract Full Text PDF PubMed Google Scholar). This element is not a classical AP-1 site but fits the consensus as a cAMP-responsive element. Previous studies suggest the involvement of AP-1 in the regulation of this element. However, even though c-Jun and c-Fos were implicated in negative control of the MyoD promoter through this element, it is not yet known what the role of a different AP-1 dimer combination could be. Our initial studies with overexpression of Fra-2 indicate that it can activate the 2.5-kb MyoD promoter containing this element, thus supporting the notion that there could be differential regulation through this element depending on the specific AP-1 dimer binding there. Additional studies of the MyoD gene have indicated the presence of a consensus AP-1 site in the middle of a region referred to as the MyoD core enhancer, which is located 20 kb away from the transcriptional start site (27.Kucharczuk K.L. Love C.M. Dougherty N.M. Goldhamer D.J. Development (Camb.). 1999; 126: 1957-1965PubMed Google Scholar). Thus, further studies dissecting the role of AP-1 dimer combinations on the MyoD promoter may be important in determining the control of MyoD expression. Considering our data, along with those of others, we propose a testable model (Fig. 6) for the inclusion of specific AP-1 complexes in a sub-circuit of the myogenic regulatory hierarchy. In this model we propose that MEF2, which is strongly induced during myogenic differentiation, activates c-Jun expression. JunD/c-Jun dimerize with Fra-2 that becomes a major component of the AP-1 complex in differentiating cells. Since Fra-2 is expressed throughout the time course of differentiation, this change in Fra-2's contribution to the AP-1 complex likely reflects post-translational control of its DNA binding properties. Fra-2-containing AP-1 complexes can then target muscle genes and also contribute to the transcriptional activation of the MRFs. The MRFs are known to be able to induce MEF2 activity; and in the current study, we also present data suggesting that one of the MRFs, MyoD, can affect the transcription of c-jun through the MEF2 element, thus completing a self-reinforcing feedback circuit. This model is based on data from the current study and those of others (18.Molkentin J.D. Black B.L. Martin J.F. Olson E.N. Cell. 1995; 83: 1125-1136Abstract Full Text PDF PubMed Scopus (698) Google Scholar, 23.Aurade F. Pfarr C.M. Lindon C. Garcia A. Primig M. Montarras D. Pinset C. J. Cell Sci. 1997; 110: 2771-2779PubMed Google Scholar, 24.Thinakaran G. Bag J. Biochem. Cell Biol. 1993; 71: 260-269Crossref PubMed Scopus (3) Google Scholar, 28.Dorman C.M. Johnson S.E. J. Biol. Chem. 2000; 275: 27481-27487Abstract Full Text Full Text PDF PubMed Google Scholar, 30.Ornatsky O.I. Andreucci J.J. McDermott J.C. J. Biol. Chem. 1997; 272: 33271-33278Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 32.Lamph W.W. Wamsley P. Sassone-Corsi P. Verma I.M. Nature. 1988; 334: 629-631Crossref PubMed Scopus (502) Google Scholar, 33.Han T. Prywes R. Mol. Cell. Biol. 1995; 15: 2907-2915Crossref PubMed Scopus (167) Google Scholar). Several studies in the early nineties suggested that AP-1 is inhibitory for myogenesis because of the observation that overexpression of c-Jun inhibits myogenesis due to a direct physical antagonism between the leucine zipper of c-Jun and the helix-loop-helix domain of MyoD (19.Li L. Chambard J. Karin M. Olson E.N. Genes Dev. 1992; 6: 676-689Crossref PubMed Scopus (186) Google Scholar, 20.Bengal E. Ransone L. Scharfmann R. Dwarki V.J. Tapscott S.J. Weintraub H. Verma I.M. Cell. 1992; 68: 507-519Abstract Full Text PDF PubMed Scopus (323) Google Scholar, 41.Su H. Bos T.J. Montecarlo F.S. Vogt P.K. Oncogene. 1991; 6: 1759-1766PubMed Google Scholar). While the physical basis for the antagonism between the two proteins when overexpressed is correct, based on our current data, we contend that these observations have masked the role of endogenous AP-1 in myogenic cells. A role for specific AP-1 complexes is not without precedent having been implicated in cellular differentiation in ovarian granulosa cells and osteoblasts (39.Sharma S.C. Richards J.S. J. Biol. Chem. 2000; 275: 33718-33728Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 40.McCabe L.R. Banerjee C. Kundu R. Harrison R.J. Dobner P.R. Stein J.L. Lian J.B. Stein G.S. Endocrinology. 1996; 137: 4398-4408Crossref PubMed Scopus (161) Google Scholar). The pleiotropic and often contradictory functional role of AP-1 raises the question of how can AP-1 mediate such contrasting processes? One possible explanation, based on evidence presented by others and ourselves, is that changes in the composition or phosphorylation of AP-1 subunits can modulate its activity such that its target genes and biological function are dynamically altered. We therefore propose that physiological levels of an AP-1 complex consisting of a JunD/Fra-2 or a c-Jun/Fra-2 heterodimer is consistent with, and not antagonistic to, myogenic differentiation. We also show data indicating that AP-1 may play a role in the full activation of MyoD expression due to direct effects on the MyoD promoter. These data implicate specific AP-1 subunits in the positive control of muscle differentiation." @default.
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