Cdc42Hs, but Not Rac1, Inhibits Serum-stimulated Cell Cycle Progression at G1/S through a Mechanism Requiring p38/RK

Abstract

Antimitogenic stimuli such as environmental or genotoxic stress, transforming growth factor-β, and the inflammatory cytokines tumor necrosis factor and interleukin-1 activate two extracellular signal-regulated kinase (ERK)-based signaling pathways: the stress-activated protein kinase (SAPK/JNK) pathway and the p38 pathway. Activated p38 phosphorylates transcription factors important in the regulation of cell growth and apoptosis, including activating transcription factor 2 (ATF2), Max, cAMP response element-binding protein-homologous protein/growth arrest DNA damage 153 (CHDP/GADD153). In turn, p38 lies downstream of the Rho family GTPases Cdc42Hs and Rac1, as well as at least three mitogen-activated protein kinase (MAPK)/ERK-kinases (MEKs): MAPK kinases-3, -6, and SAPK/ERK-kinase-1. Although many of the stimuli that activate p38 can also inhibit cell cycle progression, a clear-cut role for the p38 pathway in cell cycle regulation has not been established. Using a quantitative microinjection approach, we show here that Cdc42Hs, but not Rac1 or RhoA, can inhibit cell cycle progression at G1/S through a mechanism requiring activation of p38. These results suggest a novel role for Cdc42Hs in cell cycle inhibition. Furthermore, these results suggest that although both Cdc42Hs and Rac1 can activate p38in situ, the effects of Cdc42Hs and Rac1 on cell cycle progression are, in fact, quite distinct. Antimitogenic stimuli such as environmental or genotoxic stress, transforming growth factor-β, and the inflammatory cytokines tumor necrosis factor and interleukin-1 activate two extracellular signal-regulated kinase (ERK)-based signaling pathways: the stress-activated protein kinase (SAPK/JNK) pathway and the p38 pathway. Activated p38 phosphorylates transcription factors important in the regulation of cell growth and apoptosis, including activating transcription factor 2 (ATF2), Max, cAMP response element-binding protein-homologous protein/growth arrest DNA damage 153 (CHDP/GADD153). In turn, p38 lies downstream of the Rho family GTPases Cdc42Hs and Rac1, as well as at least three mitogen-activated protein kinase (MAPK)/ERK-kinases (MEKs): MAPK kinases-3, -6, and SAPK/ERK-kinase-1. Although many of the stimuli that activate p38 can also inhibit cell cycle progression, a clear-cut role for the p38 pathway in cell cycle regulation has not been established. Using a quantitative microinjection approach, we show here that Cdc42Hs, but not Rac1 or RhoA, can inhibit cell cycle progression at G1/S through a mechanism requiring activation of p38. These results suggest a novel role for Cdc42Hs in cell cycle inhibition. Furthermore, these results suggest that although both Cdc42Hs and Rac1 can activate p38in situ, the effects of Cdc42Hs and Rac1 on cell cycle progression are, in fact, quite distinct. Protein kinase signal transduction pathways that employ members of the extracellular signal-regulated kinase (ERK) 1The abbreviations used are: ERK, extracellular signal-regulated kinase; BrdUrd, bromodeoxyuridine; CHOP, cAMP response element binding protein-homologous protein; GADD, growth arrest DNA damage; GCK, germinal center kinase; HA, hemagglutinin; MAPK, mitogen-activated protein kinase; MAPKKK, MAPK-kinase-kinase; MEK, MAPK/ERK kinase; MEKK, MEK-kinase; MKK, MAPK-kinase (equivalent to MEK); PAK, p21-activated kinase; SAPK, stress-activated protein kinase; SAPKK, SAPK-kinase; SEK, SAPK/ERK kinase; SPRK, SH3 domain-containing, proline-rich kinase; TAK, transforming growth factor-β-activated kinase; tpl, tumor progression locus; wt, wild-type. /mitogen-activated protein kinase (MAPK) family have been remarkably conserved in evolution (1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1025) Google Scholar, 2Kyriakis J.M. Avruch J. BioEssays. 1996; 18: 567-577Crossref PubMed Scopus (661) Google Scholar, 3Herskowitz I. Cell. 1995; 80: 187-197Abstract Full Text PDF PubMed Scopus (865) Google Scholar). Typically these pathways consist of a three-tiered core of protein kinases wherein MAPK-kinase-kinases (MAPKKKs) activate MAPK/ERK kinases (MEKs), which, in turn, activate ERKs (1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1025) Google Scholar, 2Kyriakis J.M. Avruch J. BioEssays. 1996; 18: 567-577Crossref PubMed Scopus (661) Google Scholar, 3Herskowitz I. Cell. 1995; 80: 187-197Abstract Full Text PDF PubMed Scopus (865) Google Scholar). In simple eukaryotes, these pathways are activated by a variety of stresses, including nutrient withdrawal and osmotic shock (3Herskowitz I. Cell. 1995; 80: 187-197Abstract Full Text PDF PubMed Scopus (865) Google Scholar). In mammals and other multicellular eukaryotes, ERK/MAPK pathways are activated by both environmental stresses and more complex physiologic stimuli such as mitogens, developmental cues, neurotransmitters, vasoactive peptides, and inflammatory cytokines (1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1025) Google Scholar, 2Kyriakis J.M. Avruch J. BioEssays. 1996; 18: 567-577Crossref PubMed Scopus (661) Google Scholar, 4Marshall C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4236) Google Scholar). The stress-activated protein kinases (SAPKs, also referred to as JNKs) and p38 are the ERK components in two mammalian signaling pathways activated by a broad array of environmental stresses as well as by inflammatory cytokines (1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1025) Google Scholar, 2Kyriakis J.M. Avruch J. BioEssays. 1996; 18: 567-577Crossref PubMed Scopus (661) Google Scholar). Once activated, the SAPKs and p38 are responsible for the phosphorylation and activation of transcription factors necessary for the stress response including c-Jun, ATF2, Max, and CHOP (1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1025) Google Scholar, 2Kyriakis J.M. Avruch J. BioEssays. 1996; 18: 567-577Crossref PubMed Scopus (661) Google Scholar, 5Wang X. Ron D. Science. 1996; 272: 1347-1349Crossref PubMed Scopus (743) Google Scholar). The signaling components upstream of the SAPKs and p38 which have been identified thus far suggest a complex cell- and stimulus-dependent regulation consistent with the diversity of extracellular stimuli that activate these pathways. Several chromatographically distinct MEKs, including SEK1/MKK4, SAPK-kinase (SAPKK)4, and SAPKK5 can activate the SAPKs in situ andin vitro. (6Sánchez I. Hughes R.T. Mayer B.J. Yee K. Woodgett J.R. Avruch J. Kyriakis J.M. Zon L.I. Nature. 1994; 372: 794-798Crossref PubMed Scopus (916) Google Scholar, 7Moriguchi T. Kawasaki H. Matsuda S. Gotoh Y. Nishida E. J. Biol. Chem. 1995; 270: 12969-12972Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 8Meier R. Rouse J. Cuenda A. Nebreda A. Cohen P. Eur. J. Biochem. 1996; 236: 796-805Crossref PubMed Scopus (112) Google Scholar). SAPKK4 and SAPKK5 are specific for the SAPKs, whereas SEK1 can also activate p38. By contrast, MKK3 and MKK6 are specific p38 activators (8Meier R. Rouse J. Cuenda A. Nebreda A. Cohen P. Eur. J. Biochem. 1996; 236: 796-805Crossref PubMed Scopus (112) Google Scholar, 9Dérijard B. Raingeaud J. Barrett T. Wu L.-H. Han J. Ulevitch R.J. Davis R.J. Science. 1995; 267: 682-685Crossref PubMed Scopus (1413) Google Scholar, 10Raingeaud J. Whitmarsh A.J. Barrett T. Dérijard B. Davis R.J. Mol. Cell. Biol. 1996; 16: 1247-1255Crossref PubMed Scopus (1147) Google Scholar). Four families of MAPKKKs have also been implicated in SAPK and p38 regulation. MEK kinases (MEKKs) 1 and 2, as well as the mixed lineage kinase SH3 domain-containing, proline-rich kinase (SPRK), can activate the SAPK pathway via direct activation of SEK1 (11Yan M. Dai T. Deak J.C. Kyriakis J.M. Zon L.I. Woodgett J.R. Templeton D.J. Nature. 1994; 372: 798-800Crossref PubMed Scopus (658) Google Scholar, 12Blank J.L. Gerwins P. Elliott E.M. Sather S. Johnson G.L. J. Biol. Chem. 1996; 271: 5361-5368Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 13Rana A. Gallo K. Godowski P. Hirai S. Ohno S. Zon L. Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 19025-19028Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). MEKK2 can also activate the mitogenic MAPK/ERK1 and 2 pathway by directly phosphorylating the ERK1/2 upstream activator MEK1 (11Yan M. Dai T. Deak J.C. Kyriakis J.M. Zon L.I. Woodgett J.R. Templeton D.J. Nature. 1994; 372: 798-800Crossref PubMed Scopus (658) Google Scholar). Tpl-2 the rat homolog of the human cot proto-oncogene product, like MEKK2, can activate both SEK1 and MEK1 (14Salmerón A. Ahmad T.B. Carlile G.W. Pappin D. Narsimhan R.P. Ley S.C. EMBO J. 1996; 15: 817-826Crossref PubMed Scopus (269) Google Scholar). MEKK3 can activate both the SAPK and MAPK pathways, although SEK1 is not a MEKK3 substrate (11Yan M. Dai T. Deak J.C. Kyriakis J.M. Zon L.I. Woodgett J.R. Templeton D.J. Nature. 1994; 372: 798-800Crossref PubMed Scopus (658) Google Scholar). In addition, transforming growth factor-β-activated kinase-1 (TAK1) can activate p38 in situ and has been implicated as a transforming growth factor-β-activated MAPKKK upstream of SEK1, MKK3, and MKK6 (15Yamaguchi K. Shirakabe K. Shibuya H. Irie K. Oishi I. Taniguchi T. Nishida E. Matsumoto K. Science. 1995; 270: 2008-2011Crossref PubMed Scopus (1175) Google Scholar, 16Moriguchi T. Kuroyanagi N. Yamaguchi K. Gotoh Y. Irie K. 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Rac1 and the SAPKs, although to and biochemical not inhibit cell cycle progression on and in by withdrawal for of the of The by of and in with the or a microinjection R. M. and Scholar). a with the with to the by DNA R. M. and Scholar, H. M. and Scholar). at the as for or with to the DNA for and for or in the experiments in and and for Rho family activation of SAPK not cell cycle progression at G1/S via a with the and for cell cycle the of SAPK of of on cell cycle for p38 for of of with SEK1, MKK3, or are the of activation of p38 is necessary for of cell cycle and p38 of G1/S are the of p38 p38 of with the p38 and of both is in A. the to the of and not a of of p38 by directly the p38 protein with or by and as R. M. and Scholar, H. M. and Scholar). The with a by The by rat and with in as a of the of the for p38 used by a The of the the p38 or protein by or by and or stress with as A.J. A. Cell. Full Text PDF PubMed Scopus Google Scholar). by as A.J. D. A. Cell. 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In to the mitogenic pathways, which are by to the stimuli that activate the stress pathways are remarkably and DNA stress, and the inflammatory cytokines tumor necrosis and the upstream components that the p38 and SAPK pathways are complex and The Rho family GTPases Cdc42Hs and Rac1 two distinct mechanisms of p38 and SAPK activation with have that activation of Cdc42Hs cell cycle progression at as Cdc42Hs of cell cycle progression can at least of MKK3 and SEK1, we that of p38 is a of cell cycle In addition, we have that p38 or upstream of p38 MKK3, or can also arrest in By contrast, Rac1, which can also activate p38 S. Han J. Sells M.A. Chernoff J. Knaus U.G. Ulevitch R.J. Bokoch G.M. J. Biol. Chem. 1995; 270: 23934-23936Abstract Full Text Full Text PDF PubMed Scopus (651) Google A. A. A. M. Cell. 1995; 80: Full Text PDF Scopus Google to inhibit cell cycle Rac1 has been implicated in J. D. M. Nature. 1995; PubMed Scopus Google and signaling pathways that of the cell cycle or cell cycle although activation of p38 is to arrest in we that which can activated by mitogenic in with other signaling pathways, to distinct These are in the in results are in with Rho family Cdc42Hs, in cell growth and A. A. Science. 1995; PubMed Scopus Google Scholar). is that the of and Rho family signaling pathways in cell whereas activation of Cdc42Hs or in with other pathways results in cell cycle In in the of results Cdc42Hs results in suggest that is the of cell cycle progression, whereas a although growth is wild-type. the of the Cdc42Hs to mitogenic signaling including by other Rho family more the By the of Cdc42Hs, although to activate growth of of the activation for other Rho family a is a for Cdc42Hs, and Rac1 R.A. Y. Biol. 1996; PubMed Scopus Google Scholar). not that Cdc42Hs of G1/S is the of of p38 as p38 as well as MKK3, and SEK1, p38 are also to arrest at that p38 of J. A. R. J. J. 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Finally, studies that of the SAPKs or p38 results in of growth factor both the SAPKs and p38 and of or and of MKK3 or SEK1 in the of growth factor M. Raingeaud J. Davis R.J. Science. 1995; 270: PubMed Scopus Google Scholar). SAPK activation and cell in response to of SEK1 to these K. E. Zon L.I. Kyriakis J. Woodgett J.R. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). Finally, of cell with that necrosis results in apoptosis, a response that can of SEK1 M. R. B. S. E. Zon L.I. Kyriakis J.M. A. Nature. 1996; PubMed Scopus Google Scholar). these in of the experiments in 2, we of cycle arrest at apoptosis, to the response of to activation of the that to p38 J. for and Cdc42Hs J. H. Kehrl for A. Nebreda for J. Avruch for kinase and for a of the D. Ron for CHOP M. R. and S. for the for of their microinjection and the for the of their M. for