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• W1999251661 abstract "Transcriptional activation of the cyclin D1 by oncogenic Ras appears to be mediated by several pathways leading to the activation of multiple transcription factors which interact with distinct elements of the cyclin D1 promoter. The present investigations revealed that cyclin D1 induction by transforming Ha-Ras is MEK- and Rac-dependent and requires the PKC isotypes ε, λ, and ζ, but not cPKC-α. This conclusion is based on observations indicating that cyclin D1 induction by transforming Ha-Ras was depressed in a dose-dependent manner by PD98059, a selective inhibitor of the mitogen-activated kinase kinase MEK-1, demonstrating that Ha-Ras employs extracellular signal-regulated kinases (ERKs) for signal transmission to the cyclin D1 promoter. Evidence is presented that PKC isotypes ε and ζ, but not λ are required for the Ras-mediated activation of ERKs. Expression of kinase-defective, dominant negative (DN) mutants of nPKC-ε or aPKC-ζ inhibit ERK activation by constitutively active Raf-1. Phosphorylation within the TEY motif and subsequent activation of ERKs by constitutively active MEK-1 was significantly inhibited by DN aPKC-ζ, indicating that aPKC-ζ functions downstream of MEK-1 in the pathway leading to cyclin D1 induction. In contrast, TEY phosphorylation induced by constitutively active MEK-1 was not effected by nPKC-ε, suggesting another position for this kinase within the cascade investigated. Transformation by oncogenic Ras requires activation of several Ras effector pathways which may be PKC-dependent and converge on the cyclin D1 promoter. Therefore, we investigated a role for PKC isotypes in the Ras-Rac-mediated transcriptional regulation of cyclin D1. We have been able to reveal that cyclin D1 induction by oncogenic Ha-Ras is Rac-dependent and requires the PKC isotypes ε, λ, and ζ, but not cPKC-α. Evidence is presented that aPKC-λ acts upstream of Rac, between Ras and Rac, whereas the PKC isotypes ε and ζ act downstream of Rac and are required for the activation of ERKs. Transcriptional activation of the cyclin D1 by oncogenic Ras appears to be mediated by several pathways leading to the activation of multiple transcription factors which interact with distinct elements of the cyclin D1 promoter. The present investigations revealed that cyclin D1 induction by transforming Ha-Ras is MEK- and Rac-dependent and requires the PKC isotypes ε, λ, and ζ, but not cPKC-α. This conclusion is based on observations indicating that cyclin D1 induction by transforming Ha-Ras was depressed in a dose-dependent manner by PD98059, a selective inhibitor of the mitogen-activated kinase kinase MEK-1, demonstrating that Ha-Ras employs extracellular signal-regulated kinases (ERKs) for signal transmission to the cyclin D1 promoter. Evidence is presented that PKC isotypes ε and ζ, but not λ are required for the Ras-mediated activation of ERKs. Expression of kinase-defective, dominant negative (DN) mutants of nPKC-ε or aPKC-ζ inhibit ERK activation by constitutively active Raf-1. Phosphorylation within the TEY motif and subsequent activation of ERKs by constitutively active MEK-1 was significantly inhibited by DN aPKC-ζ, indicating that aPKC-ζ functions downstream of MEK-1 in the pathway leading to cyclin D1 induction. In contrast, TEY phosphorylation induced by constitutively active MEK-1 was not effected by nPKC-ε, suggesting another position for this kinase within the cascade investigated. Transformation by oncogenic Ras requires activation of several Ras effector pathways which may be PKC-dependent and converge on the cyclin D1 promoter. Therefore, we investigated a role for PKC isotypes in the Ras-Rac-mediated transcriptional regulation of cyclin D1. We have been able to reveal that cyclin D1 induction by oncogenic Ha-Ras is Rac-dependent and requires the PKC isotypes ε, λ, and ζ, but not cPKC-α. Evidence is presented that aPKC-λ acts upstream of Rac, between Ras and Rac, whereas the PKC isotypes ε and ζ act downstream of Rac and are required for the activation of ERKs. phosphatidylinositol 3-kinase dominant negative extracellular regulated kinase constitutively active mitogen-activated protein glutathioneS-transferase Transformation by oncogenic Ras requires activation of several Ras effectors which, in turn, stimulate different signaling pathways. These Ras effectors include Raf, Ral-GDS, PI 3-kinase, and Rac-1 (1Gille H. Downward J. J. Biol. Chem. 1999; 274: 22033-22040Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar). Activation of Rac-1 by oncogenic Ras is mediated by PI 3-kinase1-dependent (2Akasaki T. Koga H. Sumimoto H. J. Biol. Chem. 1999; 274: 18055-18059Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 3Genot E. Reif K. Beach S. Kramer I. Cantrell D. Oncogene. 1998; 17: 1731-1738Crossref PubMed Scopus (37) Google Scholar) and PI 3-kinase-independent mechanisms (2Akasaki T. Koga H. Sumimoto H. J. Biol. Chem. 1999; 274: 18055-18059Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). These Ras effector pathways may converge on the cyclin D1 promoter (1Gille H. Downward J. J. Biol. Chem. 1999; 274: 22033-22040Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar, 4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar). Evidence for a positive regulation of the cyclin D1 promoter by Ras has been presented (4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar, 5Lee R.J. Albanese C. Stenger R.J. Watanabe G. Inghirami G. Haines III, G.K. Webster M. Muller W.J. Brugge J.S. Davis R.J. Pestell R.G. J. Biol. Chem. 1999; 274: 7341-7350Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 6Tetsu O. McCormick F. Nature. 1999; 398: 422-426Crossref PubMed Scopus (3236) Google Scholar, 7Matsumura I. Kitamura T. Wakao H. Tanaka H. Hashimoto K. Albanese C. Downward J. Pestell R.G. Kanakura Y. EMBO J. 1999; 18: 1367-1377Crossref PubMed Scopus (290) Google Scholar).The Ras-Raf-ERK cascade has been described as the dominant pathway by which Ras transmits signals to the cyclin D1 promoter (4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar, 8Lavoie J.N. Rivard N. L'Allemain G. Pouyssegur J. Prog. Cell Cycle Res. 1996; 2: 49-58Crossref PubMed Google Scholar, 9Cheng M. Sexl V. Sherr C.J. Roussel M.F. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 1091-1096Crossref PubMed Scopus (463) Google Scholar, 10Weber J.D. Hu W. Jefcoat Jr., S.C. Raben D.M. Baldassare J.J. J. Biol. Chem. 1997; 272: 32966-32971Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar), although in nontransformed cells the situation may be different (1Gille H. Downward J. J. Biol. Chem. 1999; 274: 22033-22040Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar). One effect of the stimulation of ERK1 by Ras seems to be the activation of Ets-2, since expression of plasmids encoding DN Ets (Ets-LacZ) antagonized ERK-dependent activation of the cyclin D1 promoter (4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar) and mutation of an Ets-binding site (termed EtsB (6Tetsu O. McCormick F. Nature. 1999; 398: 422-426Crossref PubMed Scopus (3236) Google Scholar)) strongly reduced basal and also Ras-induced activation of cyclin D1.Another Ras effector, Rac-1, has also been shown to induce cyclin D1 transcription in a p65 PAK-dependent manner (11Westwick J.K. Lambert Q.T. Clark G.J. Symons M. Van Aelst L. Pestell R.G. Der C.J. Mol. Cell. Biol. 1997; 17: 1324-1335Crossref PubMed Scopus (384) Google Scholar, 12Zohn I.M. Campbell S.L. Khosravi-Far R. Rossman K.L. Der C.J. Oncogene. 1998; 17: 1415-1438Crossref PubMed Scopus (319) Google Scholar). Rac-1 also activates c-Jun NH2-terminal kinase, which in turn activates the JUN members of the AP-1 transcription factor family. AP-1 transcription factors activate the cyclin D1 promoter through a critical AP-1 site (4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar, 13Watanabe G. Howe A. Lee R.J. Albanese C. Shu I.W. Karnezis A.N. Zon L. Kyriakis J. Rundell K. Pestell R.G. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 12861-12866Crossref PubMed Scopus (195) Google Scholar).In addition to the AP-1 site, a CRE site (13Watanabe G. Howe A. Lee R.J. Albanese C. Shu I.W. Karnezis A.N. Zon L. Kyriakis J. Rundell K. Pestell R.G. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 12861-12866Crossref PubMed Scopus (195) Google Scholar, 14Brown J.R. Nigh E. Lee R.J. Ye H. Thompson M.A. Saudou F. Pestell R.G. Greenberg M.E. Mol. Cell. Biol. 1998; 18: 5609-5619Crossref PubMed Scopus (207) Google Scholar) is involved in induction of cyclin D1 transcription triggered by Ras (6Tetsu O. McCormick F. Nature. 1999; 398: 422-426Crossref PubMed Scopus (3236) Google Scholar), pp60 src (5Lee R.J. Albanese C. Stenger R.J. Watanabe G. Inghirami G. Haines III, G.K. Webster M. Muller W.J. Brugge J.S. Davis R.J. Pestell R.G. J. Biol. Chem. 1999; 274: 7341-7350Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), or SV40 small T antigen (13Watanabe G. Howe A. Lee R.J. Albanese C. Shu I.W. Karnezis A.N. Zon L. Kyriakis J. Rundell K. Pestell R.G. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 12861-12866Crossref PubMed Scopus (195) Google Scholar). The CRE-binding protein is activated by several kinases including ERK 1/2 and a p38-dependent kinase cascade triggered by Rac-1 (15De Cesare D. Fimia G.M. Sassone-Corsi P. Trends Biochem. Sci. 1999; 24: 281-285Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar).Thus, transcriptional activation of the cyclin D1 promoter by oncogenic Ras appears to be mediated by several pathways leading to the activation of multiple transcription factors which interact with distinct elements of the cyclin D1 promoter. Whether PKCs are involved in signal transmission from Ras to the cyclin D1 promoter has remained unclear.PKCs represent a family of structurally related serine/threonine protein kinases known to comprise 11 isotypes. The various PKC isoforms are classified into three major subgroups: (i) the classical or conventional PKC isoforms (cPKCs) which are Ca2+- and diacylglycerol-dependent, namely cPKC-α, cPKC-β1, cPKC-β2, and cPKC-γ; (ii) Ca2+-independent, but diacylglycerol-responsive PKC isotypes that have been termed novel PKCs (nPKCs) and comprise the isozymes nPKC-δ, nPKC-ε, and nPKC-θ; and (iii) the so-called atypical PKC isoforms that require neither Ca2+ nor diacylglycerol for activation and currently known to comprise aPKC-λ/ι and aPKC-ζ (16Ron D. Kazanietz M.G. FASEB J. 1999; 13: 1658-1676Crossref PubMed Scopus (551) Google Scholar).PKC isotypes have been shown to be implicated in Ras-mediated induction of c-fos (17Kampfer S. Hellbert K. Villunger A. Doppler W. Baier G. Grunicke H.H. Überall F. EMBO J. 1998; 17: 4046-4055Crossref PubMed Scopus (62) Google Scholar), activation of Raf-1 (17Kampfer S. Hellbert K. Villunger A. Doppler W. Baier G. Grunicke H.H. Überall F. EMBO J. 1998; 17: 4046-4055Crossref PubMed Scopus (62) Google Scholar, 18Cai H. Smola U. Wixler V. Eisenmann-Tappe I. Diaz-Meco M.T. Moscat J. Rapp U. Cooper G.M. Mol. Cell. Biol. 1997; 17: 732-741Crossref PubMed Scopus (263) Google Scholar), receptor tyrosine kinase, and Raf-mediated stimulation of ERK 1/2 (17Kampfer S. Hellbert K. Villunger A. Doppler W. Baier G. Grunicke H.H. Überall F. EMBO J. 1998; 17: 4046-4055Crossref PubMed Scopus (62) Google Scholar, 19Marquardt B. Frith D. Stabel S. Oncogene. 1994; 9: 3213-3218PubMed Google Scholar, 20Berra E. Diaz-Meco M.T. Lozano J. Frutos S. Municio M.M. Sanchez P. Sanz L. Moscat J. EMBO J. 1995; 14: 6157-6163Crossref PubMed Scopus (252) Google Scholar, 21Liao D.F. Monia B. Dean N. Berk B.C. J. Biol. Chem. 1997; 272: 6146-6150Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 22Sajan M.P. Standaert M.L. Bandyopadhyay G. Quon M.J. Burke Jr., T.R. Farese R.V. J. Biol. Chem. 1999; 274: 30495-30500Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), RhoA, and Rac-1, as well as PI 3-kinase-dependent reorganization of the actin cytoskeleton (23Überall F. Hellbert K. Kampfer S. Maly K. Villunger A. Spitaler M. Mwanjewe J. Baier-Bitterlich G. Baier G. Grunicke H.H. J. Cell Biol. 1999; 144: 413-425Crossref PubMed Scopus (125) Google Scholar). Furthermore, evidence is presented that atypical aPKC-λ and -ζ associate with Cdc42 in a GTP-dependent manner, but use different pathways as Rac for the reorganization of F-actin stress fibers (24Coghlan M.P. Chou M.M. Carpenter C.L. Mol. Cell. Biol. 2000; 20: 2880-2889Crossref PubMed Scopus (83) Google Scholar).In view of all these reports we investigated whether PKC isoenzymes are playing a functional role in the transcriptional activation of cyclin D1 by transforming Ras. In this paper evidence is presented that transcriptional activation of cyclin D1 by oncogenic Ras is MEK-1-, and Rac-1-dependent and requires aPKC-λ, nPKC-ε, and aPKC-ζ, but not cPKC-α.The data support a tentative model for different signaling pathways in which aPKC-λ acts upstream of Rac-1 and MEK-1, whereas PKC-ζ is required for the activation of ERKs working downstream of MEK-1. Expression of a DN mutant of nPKC-ε inhibits ERK activation by constitutively active (CA) Raf-1, but ERK TEY phosphorylation induced by CA MEK-1 was not effected by nPKC-ε, suggesting another position of nPKC-ε within the cascade investigated.DISCUSSIONThe data presented here demonstrate that in HC11 cells, transcriptional activation of cyclin D1 by transforming L61 Ha-Ras is MEK-1-, and Rac-1-dependent and requires the three PKC isozymes λ, ε and ζ. This conclusion is based on the observation that DN mutants of aPKC-λ, nPKC-ε, and aPKC-ζ inhibit cyclin D1 induction by transforming Ras, whereas CA mutants of these enzyme family were found to activate cyclin D1 by a Ras-independent mechanism (data not shown).PKC-α which is also expressed in HC11 cells, is not employed by Ras for the induction of cyclin D1. Neither DN nor CA versions of cPKC-α were found to affect cyclin D1 induction by Ras.As suggested in our recent publication (23Überall F. Hellbert K. Kampfer S. Maly K. Villunger A. Spitaler M. Mwanjewe J. Baier-Bitterlich G. Baier G. Grunicke H.H. J. Cell Biol. 1999; 144: 413-425Crossref PubMed Scopus (125) Google Scholar), aPKC-λ acts upstream of Rac in Ras-mediated reorganization of the F-actin cytoskeleton. PKC isotypes ε and ζ were found to function downstream of Raf-1 (17Kampfer S. Hellbert K. Villunger A. Doppler W. Baier G. Grunicke H.H. Überall F. EMBO J. 1998; 17: 4046-4055Crossref PubMed Scopus (62) Google Scholar).The Ras-Raf pathways have been shown to be interconnected by PAK (31Chaudhary A. King W.G. Mattaliano M.D. Frost J.A. Diaz B. Morrison D.K. Cobb M.H. Marshall M.S. Brugge J.S. Curr. Biol. 2000; 10: 551-554Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Activation of PAK by Rac is considered essential for cyclin D1 induction by Rac, whereas activation of c-Jun NH2-terminal kinase or p38 were found to be dispensable for cyclin D1 induction by Rac (11Westwick J.K. Lambert Q.T. Clark G.J. Symons M. Van Aelst L. Pestell R.G. Der C.J. Mol. Cell. Biol. 1997; 17: 1324-1335Crossref PubMed Scopus (384) Google Scholar). PAK-1 has been shown to phosphorylate and enhance the activity of MEK-1 (32Frost J.A. Steen H. Shapiro P. Lewis T. Ahn N. Shaw P.E. Cobb M.H. EMBO J. 1997; 16: 6426-6438Crossref PubMed Scopus (359) Google Scholar). Thus, Ras may require the Rac > PAK > MEK pathway for a full activation of ERK 1/2. Overexpression of ERK-1 directly induced cyclin D1 (4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar). All these findings indicate that ERKs are involved in transcriptional activation of cyclin D1 by Ras, as well as by Rac.In our system the MEK-1 specific inhibitor PD098059 significantly inhibited transcriptional activation of cyclin D1 by Ras. PD098059 abrogated transcriptional activation by Ras when both, the AP-1 and the CRE sites were deleted, demonstrating that under these conditions the Ras-Raf-ERK pathway, presumably resulting in activation of an Ets site, is predominant for signal transmission from Ras to the cyclin D1 promoter. This is in agreement with the findings reported by others (4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar), indicating that ERK induction of cyclin D1 was blocked by dominant negative Ets.We previously demonstrated that PKC isozymes ε and ζ act downstream of Raf-1 in the Ras-Raf-MEK-ERK pathway activating transcription of c-fos (17Kampfer S. Hellbert K. Villunger A. Doppler W. Baier G. Grunicke H.H. Überall F. EMBO J. 1998; 17: 4046-4055Crossref PubMed Scopus (62) Google Scholar). The data presented here further enlarge the assumption that PKC isotypes ε and ζ are involved in the activation of ERKs by Ras and are in agreement with data published by others (20Berra E. Diaz-Meco M.T. Lozano J. Frutos S. Municio M.M. Sanchez P. Sanz L. Moscat J. EMBO J. 1995; 14: 6157-6163Crossref PubMed Scopus (252) Google Scholar,33Huang C. Li J. Chen N. Ma W. Bowden G.T. Dong Z. Mol. Carcinog. 2000; 27: 65-75Crossref PubMed Scopus (43) Google Scholar, 34Skaletz-Rorowski A. Waltenberger J. Muller J.G. Pawlus E. Pinkernell K. Breithardt G. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 1608-1614Crossref PubMed Scopus (20) Google Scholar, 35Ping P. Zhang J. Cao X. Li R.C. Kong D. Tang X.L. Qiu Y. Manchikalapudi S. Auchampach J.A. Black R.G. Bolli R. Am. J. Physiol. 1999; 276: H1468-H1481PubMed Google Scholar, 36Takeda H. Matozaki T. Takada T. Noguchi T. Yamao T. Tsuda M. Ochi F. Fukunaga K. Inagaki K. Kasuga M. EMBO J. 1999; 18: 386-395Crossref PubMed Scopus (137) Google Scholar, 37Traub O. Monia B.P. Dean N.M. Berk B.C. J. Biol. Chem. 1997; 272: 31251-31257Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 38Schönwasser D.C. Marais R.M. Marshall C.J. Parker P.J. Mol. Cell. Biol. 1998; 18: 790-798Crossref PubMed Scopus (674) Google Scholar, 39Mitev V. Le Panse R. Coulomb B. Miteva L. Houdebine L.M. Biochem. Biophys. Res. Commun. 1995; 208: 245-252Crossref PubMed Scopus (24) Google Scholar).The molecular mechanism by which PKC stimulates ERK is, however, still unclear. It was demonstrated that conventional and novel PKCs (α and ε) are potent activators of c-Raf-1, whereas atypical aPKC-ζ stimulates MEK by a different mechanism (20Berra E. Diaz-Meco M.T. Lozano J. Frutos S. Municio M.M. Sanchez P. Sanz L. Moscat J. EMBO J. 1995; 14: 6157-6163Crossref PubMed Scopus (252) Google Scholar, 38Schönwasser D.C. Marais R.M. Marshall C.J. Parker P.J. Mol. Cell. Biol. 1998; 18: 790-798Crossref PubMed Scopus (674) Google Scholar).DN PKC-ζ strongly inhibits phosphorylation and activation of ERK 1/2 by CA MEK-1, indicating that aPKC-ζ functions downstream of MEK-1. This assumption is further strengthened by the fact that aPKC-ζ does not physically interact with MEK-1 in pull-down experiments (data not shown). The mechanism by which nPKC-ε and aPKC-ζ regulate ERK activation remains to be elucidated. A direct PKC-catalyzed phosphorylation of ERKs could be excluded. Furthermore, no evidence for an inhibition of MAP kinase phosphatases by PKC isotypes could be detected (not shown).Another model which is presently under investigation, concerns a PKC-regulated interaction with scaffold proteins which may be essential for the selective activation of ERKs (40Leinweber B.D. Leavis P.C. Grabarek Z. Wang C.L. Morgan K.G. Biochem. J. 1999; 344: 117-123Crossref PubMed Scopus (124) Google Scholar, 41Ito M. Yoshioka K. Akechi M. Yamashita S. Takamatsu N. Sugiyama K. Hibi M. Nakabeppu Y. Shiba T. Yamamoto K.I. Mol. Cell. Biol. 1999; 19: 7539-7548Crossref PubMed Scopus (225) Google Scholar, 42Kelkar N. Gupta S. Dickens M. Davis R.J. Mol. Cell. Biol. 2000; 20: 1030-1043Crossref PubMed Scopus (249) Google Scholar, 43Arudchandran R. Brown M.J. Peirce M.J. Song J.S. Zhang J. Siraganian R.P. Blank U. Rivera J. J. Exp. Med. 2000; 191: 47-60Crossref PubMed Scopus (74) Google Scholar). As recently reported Ha-Ras employs the same PKC isotypes for the induction of c-fos (17Kampfer S. Hellbert K. Villunger A. Doppler W. Baier G. Grunicke H.H. Überall F. EMBO J. 1998; 17: 4046-4055Crossref PubMed Scopus (62) Google Scholar). Evidence for a functional role of c-fos in the transcriptional regulation of cyclin D1 has been published (14Brown J.R. Nigh E. Lee R.J. Ye H. Thompson M.A. Saudou F. Pestell R.G. Greenberg M.E. Mol. Cell. Biol. 1998; 18: 5609-5619Crossref PubMed Scopus (207) Google Scholar, 44Kovary K. Bravo R. Mol. Cell. Biol. 1991; 11: 4466-4472Crossref PubMed Scopus (393) Google Scholar, 45Won K.A. Xiong Y. Beach D. Gilman M.Z. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9910-9914Crossref PubMed Scopus (267) Google Scholar). Thus, it may appear that the findings presented here simply reflect a requirement for c-fosin the transcriptional activation of cyclin D1, but the following considerations, however, suggest that this is not the case.The cyclin D1 promoter contains two sites that could mediate a direct induction by c-Fos: a classical AP-1 site (at approximately −950) and a CRE/ATF site at approximately −60 (4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar, 28Herber B. Truss M. Beato M. Muller R. Oncogene. 1994; 9: 1295-1304PubMed Google Scholar). Both sites have been shown to bind c-Fos containing heterodimers (4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar, 14Brown J.R. Nigh E. Lee R.J. Ye H. Thompson M.A. Saudou F. Pestell R.G. Greenberg M.E. Mol. Cell. Biol. 1998; 18: 5609-5619Crossref PubMed Scopus (207) Google Scholar).These findings were confirmed by us in HC11 cells where stimulation of the Ras pathway by epidermal growth factor was shown to result in binding of c-Fos/c-Jun heterodimers to both the AP-1 and the CRE sites (not shown). The observation that deletion of both the AP-1 and the CRE sites neither depressed cyclin D1 induction by Ras nor abolished the PKC dependence of Ras-mediated transcriptional activation, suggests that transcriptional induction of c-fos is not sufficient for cyclin D1 induction by oncogenic Ha-Ras. Candidates for additional sites are Ets-binding domains and E2F sites. Multiple putative Ets-binding sites can be detected within the cyclin D1 promoter. Ets sites essential for Ras-mediated cyclin D1 induction have been located at position −778 (6Tetsu O. McCormick F. Nature. 1999; 398: 422-426Crossref PubMed Scopus (3236) Google Scholar) and within the proximal promoter region (4Albanese C. Johnson J. Watanabe G. Eklund N. Vu D. Arnold A. Pestell R.G. J. Biol. Chem. 1995; 270: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar). Mutation of a E2F site located in a truncated cyclin D1 promoter lacking the sequence upstream of position −163 strongly reduced the responsiveness to transcriptional activation by Neu (46Lee R.J. Albanese C. Fu M. D'Amico M. Lin B. Watanabe G. Haines III, G.K. Siegel P.M. Hung M.C. Yarden Y. Horowitz J.M. Muller W.J. Pestell R.G. Mol. Cell. Biol. 2000; 20: 672-683Crossref PubMed Scopus (307) Google Scholar).In agreement with a previous publication (11Westwick J.K. Lambert Q.T. Clark G.J. Symons M. Van Aelst L. Pestell R.G. Der C.J. Mol. Cell. Biol. 1997; 17: 1324-1335Crossref PubMed Scopus (384) Google Scholar), it was also found that transforming Ha-Ras employs the Ras-homology protein Rac-1 for transcriptional activation of cyclin D1. DN N17-Rac-1 blocked Ras-mediated induction of cyclin D1 and CA V12-Rac activated transcription of cyclin D1 in the absence of transforming Ras. Induction of cyclin D1 by V12-Rac is depressed by DN mutants of nPKC-ε and aPKC-ζ, but not, however, by DN aPKC-λ, indicating that PKC isotypes ε and ζ act downstream of Rac. The inhibitory effect of DN aPKC-λ, however, was overcome by V12-Rac, whereas V12-Rac had no effect on the suppression of Ras-mediated cyclin D1 induction by DN PKC isoforms ε and ζ. Therefore, it can be concluded that aPKC-λ acts upstream of Rac-1, whereas PKC isozymes ε and ζ function downstream of Rac-1.The ability of Rac-1 to bind and activate p21-activated kinase p65 PAK was shown to correlate with its ability for transcriptional activation of the cyclin D1 promoter (11Westwick J.K. Lambert Q.T. Clark G.J. Symons M. Van Aelst L. Pestell R.G. Der C.J. Mol. Cell. Biol. 1997; 17: 1324-1335Crossref PubMed Scopus (384) Google Scholar). It has also been reported that signals from Ras and Rac converge on PAK and evidence for a signaling pathway Ras > Rac > PAK has been presented (47Tang Y., Yu, J. Field J. Mol. Cell. Biol. 1999; 19: 1881-1891Crossref PubMed Scopus (120) Google Scholar), suggesting that Ras activates transcription of cyclin D1 predominantly via Rac.If this is correct, Ras and Rac should activate cyclin D1 transcription through the same promoter elements. This, however, was not found to be the case. Since Ras could activate the mutated promoter as efficient as the wild type promoter we have suggested that under these conditions signal transmission from Ras to the cyclin D1 promoter involves other sites.In HC11 cells, Rac-1 partially activates transcription of cyclin D1 through AP-1 and CRE sites. In accordance with findings by others (31Chaudhary A. King W.G. Mattaliano M.D. Frost J.A. Diaz B. Morrison D.K. Cobb M.H. Marshall M.S. Brugge J.S. Curr. Biol. 2000; 10: 551-554Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar), our data suggest that Rac-1 additionally is involved in the pathway from Ras to the cyclin D1 promoter via the Ras > Raf > ERK cascade, presumably by activating p65 PAK-1 (32Frost J.A. Steen H. Shapiro P. Lewis T. Ahn N. Shaw P.E. Cobb M.H. EMBO J. 1997; 16: 6426-6438Crossref PubMed Scopus (359) Google Scholar). The recent suggestion that PAK-3 could stimulate Raf-1 activity by directly phosphorylating Ser-338 through a Ras-phosphatidylinositol 3-kinase/Cdc42-dependent pathway has attracted much attention (48Chiloeches A. Mason C.S. Marais R. Mol. Cell. Biol. 2001; 21: 2423-2434Crossref PubMed Scopus (65) Google Scholar). However, in HC11 cells, this pathway seems to be of minor importance, as the PI 3-kinase inhibitors wortmannin and LY 294002 did not interfere with cyclin D1 induction by Ras (not shown).In addition to these sites, binding elements for several other transcription factors have been identified within the cyclin D1 promoter, comprising sites for Sp1, TCF/LEF-1, NF-κB, E2F, Ets, and STAT5 (6Tetsu O. McCormick F. Nature. 1999; 398: 422-426Crossref PubMed Scopus (3236) Google Scholar, 7Matsumura I. Kitamura T. Wakao H. Tanaka H. Hashimoto K. Albanese C. Downward J. Pestell R.G. Kanakura Y. EMBO J. 1999; 18: 1367-1377Crossref PubMed Scopus (290) Google Scholar, 28Herber B. Truss M. Beato M. Muller R. Oncogene. 1994; 9: 1295-1304PubMed Google Scholar, 29Shtutman M. Zhurinsky J. Simcha I. Albanese C. D'Amico M. Pestell R. Ben Ze'ev A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 5522-5527Crossref PubMed Scopus (1906) Google Scholar, 30Hinz M. Krappmann D. Eichten A. Heder A. Scheidereit C. Strauss M. Mol. Cell. Biol. 1999; 19: 2690-2698Crossref PubMed Scopus (698) Google Scholar, 49Guttridge D.C. Albanese C. Reuther J.Y. Pestell R.G. Baldwin Jr., A.S. Mol. Cell. Biol. 1999; 19: 5785-5799Crossref PubMed Google Scholar). The biological function of PKC isotypes involved in pathways corresponding with these additionally described factors remains to be elucidated.The observations described in this paper allow us to draw novel and exiting models for the regulation of cyclin D1 by PKCs, however, they also raise many questions that need to be addressed. For example, how can we explain that aPKC-ζ is involved in signal transmission from Ras to cyclin D1 without direct interaction of MEK-1 and/or phosphorylation events necessary for ERK activation. Genetic models, including conditional PKC knock-out mice, will give us more information concerning the biological functions of the PKC isotypes found in these pathways. Experiments in this direction are under way. Together with findings from others (50Yu Q. Geng Y. Sicinski P. Nature. 2001; 411: 1017-1021Crossref PubMed Scopus (824) Google Scholar), explaining the absolute dependence on cyclin D1 from Neu- and Ras-mediated malignant transformation in mammary epithelial cells, intervention of breast cancer with PKC isotype-specific inhibitors might be a promising therapeutical approach. Transformation by oncogenic Ras requires activation of several Ras effectors which, in turn, stimulate different signaling pathways. These Ras effectors include Raf, Ral-GDS, PI 3-kinase, and Rac-1 (1Gille H. Downward J. J. Biol. Chem. 1999; 274: 22033-22040Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar). Activation of Rac-1 by oncogenic Ras is mediated by PI 3-kinase1-dependent (2Akasaki T. Koga H. Sumimoto H. J. Biol. Chem. 1999; 274: 18055-18059Abstract Full Text Full Text PDF PubM" @default.
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