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• W2030254491 abstract "The Bcl-2 family member Bad is a pro-apoptotic protein, and phosphorylation of Bad by cytokines and growth factors promotes cell survival in many cell types. Induction of apoptosis by UV radiation is well documented. However, little is known about UV activation of cell survival pathways. Here, we demonstrate that UVB induces Bad phosphorylation at serine 112 in JNK1, RSK2, and MSK1-dependent pathways. Inhibition of mitogen-activated protein (MAP) kinases including ERKs, JNKs, and p38 kinase by the use of their respective dominant negative mutant or a specific inhibitor for MEK1 or p38 kinase, PD98059 or SB202190, resulted in abrogation of UVB-induced phosphorylation of Bad at serine 112. Incubation of active MAP kinase members with Bad protein showed serine 112 phosphorylation of Bad by JNK1 only. However, activated RSK2 and MSK1, downstream kinases of ERKs and p38 kinase, respectively, also phosphorylated Bad at serine 112 in vitro. Cells from a Coffin-Lowry syndrome patient (deficient in RSK2) or expressing an N-terminal or C-terminal kinase-dead mutant of MSK1 were defective for UVB-induced serine 112 phosphorylation of Bad. Furthermore, MAP kinase pathway-dependent serine 112 phosphorylation was shown to be required for dissociation of Bad from Bcl-XL. These data illustrated that UVB-induced phosphorylation of Bad at serine 112 was mediated through MAP kinase signaling pathways in which JNK1, RSK2, and MSK1 served as direct mediators. The Bcl-2 family member Bad is a pro-apoptotic protein, and phosphorylation of Bad by cytokines and growth factors promotes cell survival in many cell types. Induction of apoptosis by UV radiation is well documented. However, little is known about UV activation of cell survival pathways. Here, we demonstrate that UVB induces Bad phosphorylation at serine 112 in JNK1, RSK2, and MSK1-dependent pathways. Inhibition of mitogen-activated protein (MAP) kinases including ERKs, JNKs, and p38 kinase by the use of their respective dominant negative mutant or a specific inhibitor for MEK1 or p38 kinase, PD98059 or SB202190, resulted in abrogation of UVB-induced phosphorylation of Bad at serine 112. Incubation of active MAP kinase members with Bad protein showed serine 112 phosphorylation of Bad by JNK1 only. However, activated RSK2 and MSK1, downstream kinases of ERKs and p38 kinase, respectively, also phosphorylated Bad at serine 112 in vitro. Cells from a Coffin-Lowry syndrome patient (deficient in RSK2) or expressing an N-terminal or C-terminal kinase-dead mutant of MSK1 were defective for UVB-induced serine 112 phosphorylation of Bad. Furthermore, MAP kinase pathway-dependent serine 112 phosphorylation was shown to be required for dissociation of Bad from Bcl-XL. These data illustrated that UVB-induced phosphorylation of Bad at serine 112 was mediated through MAP kinase signaling pathways in which JNK1, RSK2, and MSK1 served as direct mediators. interleukin cytomegalovirus dominant negative Coffin-Lowry syndrome c-Jun N-terminal kinase extracellular signal-regulated protein kinase mitogen-activated protein mitogen-activated protein kinase kinase 1 p90 ribosomal S6 kinase 2 mitogen- and stress-activated protein kinase 1 mitogen-activated protein kinase-activated protein kinase 2 phosphatidylinositol 3-kinase p21-activated protein kinase protein kinase A Eagle's minimum essential medium fetal bovine serum tumor necrosis factor 4-morpholinepropanesulfonic acid The development and maintenance of healthy tissues is critically dependent on a balance between cell survival and cell death (apoptosis). Alterations of both pathways contribute to the clonal expansion of cancer cells. The Bcl-2 family of related proteins contains protein-protein interaction domains that facilitate homo- and heterodimerization. Some members, Bcl-2, Bcl-XL, Mcl-1, and A1, promote cell survival, whereas others, Bad, Bid, Bax, and Bak, promote cell death. A possible mechanism exists whereby the interactions resulting in homo- or heterodimerization of the various proteins define the fate of a cell (1Oltvai Z.N. Korsmeyer S.J. Cell. 1994; 79: 189-192Abstract Full Text PDF PubMed Scopus (773) Google Scholar, 2Reed J.C. Oncogene. 1998; 17: 3225-3236Crossref PubMed Scopus (936) Google Scholar). Bad, for example, has been shown to heterodimerize with Bcl-XL through interaction with its Bcl-2 homology 3 domain at the mitochondrial membrane (3Zha J. Harada H. Osipov K. Jockel J. Waksman G. Korsmeyer S.J. J. Biol. Chem. 1997; 272: 24101-24104Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 4Kelekar A. Chang B.S. Harlan J.E. Fesik S.W. Thompson C.B. Mol. Cell. Biol. 1997; 17: 7040-7046Crossref PubMed Scopus (269) Google Scholar). The complex formation of Bad with Bcl-XL may cause Bcl-XL to release Apaf1 or regulate other Bcl-XL activities resulting in a caspase 9-initiated cascade of proteolysis and induction of apoptosis (5Gross A. McDonnell J.M. Korsmeyer S.J. Genes Dev. 1999; 13: 1899-1911Crossref PubMed Scopus (3238) Google Scholar, 6Martin S.J. Green D.R. Cell. 1995; 82: 349-352Abstract Full Text PDF PubMed Scopus (1258) Google Scholar). Survival factors such as interleukin (IL)1-3 can inhibit the apoptotic activity of Bad by activating intracellular signaling pathways that result in the phosphorylation of Bad at two critical sites, serine 112 and serine 136 (7Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar). Akt has been shown to promote cell survival through its ability to phosphorylate Bad specifically at serine 136 (8Datta S.R. Dudek H. Tao X. Masters S., Fu, H. Gotoh Y. Greenberg M.E. Cell. 1997; 91: 231-241Abstract Full Text Full Text PDF PubMed Scopus (4914) Google Scholar, 9del Peso L. Gonzalez-Garcia M. Page C. Herrera R. Nunez G. Science. 1997; 278: 687-689Crossref PubMed Scopus (1978) Google Scholar). Recent studies showed that RSK2 (p90 ribosomal S6 kinase 2), mitochondria-associated protein kinase A (PKA), and α- or γ-p21-activated protein kinase (PAK) can mediate cytokine or growth factor-induced phosphorylation of Bad at serine 112 (10Bonni A. Brunet A. West A.E. Datta S.R. Takasu M.A. Greenberg M.E. Science. 1999; 286: 1358-1362Crossref PubMed Scopus (1664) Google Scholar, 11Tan Y. Ruan H. Demeter M.R. Comb M.J. J. Biol. Chem. 1999; 274: 34859-34867Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 12Harada H. Becknell B. Wilm M. Mann M. Huang L.J. Taylor SS Scott J.D. Korsmeyer S.J. Mol. Cell. 1999; 3: 413-422Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar). Phosphorylation of Bad at serine residues 112 and 136 leads to the dissociation of Bad from pro-survival Bcl-XL protein (7Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar). Mutation of either of these residues to alanine potentiates cell death following transient transfection with Bad, suggesting that both are critical in the disruption of Bad-Bcl-XL heterodimers.Ultraviolet (UV) radiation, especially in the UVB range (290–320 nm), is an important environmental factor of inducible health hazards for mankind, which include the induction of skin cancer (15de Gruijl F.R. Sterenborg H.J. Forbes P.D. Davies R.E. Cole C Kelfkens G. van Weelden H. Slaper H. van der Leun J.C. Cancer Res. 1993; 53: 53-60PubMed Google Scholar), suppression of the immune system (16Beissert S. Schwarz T. J. Invest. Dermatol. Symp. Proc. 1999; 4: 61-64Abstract Full Text PDF PubMed Scopus (120) Google Scholar), and chronic skin damage including premature skin aging (17Fisher G.J. Datta S.C. Talwar H.S. Wang Z.Q. Varani J. Kang S Voorhees J.J. Nature. 1996; 379: 335-339Crossref PubMed Scopus (1181) Google Scholar). Similar to chemical agents, UV has the ability to activate various signal transduction pathways and to induce the expression of specific genes (18Herrlich P. Ponta H. Rahmsdorf H.J. Rev. Physiol. Biochem. Pharmacol. 1992; 119: 187-223Crossref PubMed Scopus (182) Google Scholar, 19Herrlich P. Rahmsdorf H.J. Curr. Opin. Cell Biol. 1994; 6: 425-431Crossref PubMed Scopus (51) Google Scholar, 20Bender K. Blattner C. Knebel A. Iordanov M. Herrlich P. Rahmsdorf H.J. J. Photochem. Photobiol. B Biol. 1997; 37: 1-17Crossref PubMed Scopus (233) Google Scholar). A great deal of progress has been made recently in elucidating the mechanisms of the UV-induced apoptotic signaling transduction pathways (21Tournier C. Hess P. Yang D.D., Xu, J. Turner T.K. Nimnual A Bar-Sagi D. Jones S.N. Flavell R.A. Davis R.J. Science. 2000; 288: 870-874Crossref PubMed Scopus (1535) Google Scholar, 22Bulavin D.V. Saito S. Hollander M.C. Sakaguchi K. Anderson CW Appella E. Fornace A.J., Jr. EMBO J. 1999; 18: 6845-6854Crossref PubMed Scopus (593) Google Scholar). However, much less is known about the UV-induced survival-signaling pathway, especially during the immediate time following UV radiation.One of the major UV responsive pathways is the Ras/mitogen-activated protein (MAP) kinases cascade (23Dhanasekaran N. Premkumar Reddy E. Oncogene. 1998; 17: 1447-1455Crossref PubMed Scopus (249) Google Scholar). MAP kinases belong to a large family of serine/threonine protein kinases comprising three distinct components: extracellular-signal-regulated protein kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 kinase. Generally, JNKs and p38 kinase are known to be activated by various forms of stress, such as UV radiation, heat shock, and inflammation (24Derijard B. Hibi M., Wu, I.H. Barrett T., Su, B. Deng T. Karin M. Davis R.J. Cell. 1994; 76: 1025-1037Abstract Full Text PDF PubMed Scopus (2949) Google Scholar, 25Han J. Lee J.D. Bibbs L. Ulevitch R.J. Science. 1994; 265: 808-811Crossref PubMed Scopus (2401) Google Scholar, 26Rosette C. Karin M. Science. 1996; 274: 1194-1197Crossref PubMed Scopus (941) Google Scholar). Our studies and those of others have shown that ERKs are critical for UV-induced signal transduction (27Huang C., Ma, W.Y. Dong Z. Oncogene. 1999; 18: 2828-2835Crossref PubMed Scopus (63) Google Scholar, 28She Q.B. Chen N. Dong Z. J. Biol. Chem. 2000; 275: 20444-20449Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar, 29Merienne K. Jacquot S. Zeniou M. Pannetier S. Sassone-Corsi P. Hanauer A. Oncogene. 2000; 19: 4221-4229Crossref PubMed Scopus (39) Google Scholar). Although UVB radiation has been shown to induce cytokine production (30Kock A. Schwarz T. Kirnbauer R. Urbanski A. Perry P. Ansel J.C. Luger T.A. J. Exp. Med. 1990; 172: 1609-1614Crossref PubMed Scopus (635) Google Scholar, 31Ullrich S.E. Photochem. Photobiol. 1995; 62: 389-401Crossref PubMed Scopus (122) Google Scholar, 32Leverkus M. Yaar M. Eller M.S. Tang E.H. Gilchrest B.A. J. Invest. Dermatol. 1998; 110: 353-357Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 33Kulms D. Poppelmann B. Schwarz T. J. Biol. Chem. 2000; 275: 15060-15066Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar) and to activate growth factor and cytokine receptors (26Rosette C. Karin M. Science. 1996; 274: 1194-1197Crossref PubMed Scopus (941) Google Scholar), whether UVB radiation induces Bad phosphorylation and the signaling pathways that are involved in the phosphorylation remains largely unknown. MAP kinases have been implicated in both apoptosis and survival signaling (34Xia Z. Dickens M. Raingeaud J. Davis R.J. Greenberg M.E. Science. 1995; 270: 1326-1331Crossref PubMed Scopus (5027) Google Scholar, 35Ip Y.T. Davis R.J. Curr. Opin. Cell Biol. 1998; 10: 205-219Crossref PubMed Scopus (1374) Google Scholar, 36Roulston A. Reinhard C. Amiri P. Williams L.T. J. Biol. Chem. 1998; 273: 10232-10239Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar, 37Zechner D. Craig R. Hanford D.S. McDonough P.M. Sabbadini RA Glembotski C.C. J. Biol. Chem. 1998; 273: 8232-8239Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Therefore, we investigated the possible role of MAP kinase signaling pathways in the regulation of Bad phosphorylation and its function following UVB radiation. In this study, we demonstrated that UVB radiation induces Bad phosphorylation at serine 112, but not serine 136. Using a dominant negative mutant of ERK2, JNK1, p38 kinase, or an N-terminal or C-terminal kinase-dead mutant of mitogen- and stress-activated protein kinase 1 (MSK1), RSK2-deficient cells, and a specific inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) or p38 kinase, we conclude that UVB-induced phosphorylation of Bad at serine 112 is mediated through MAP kinase signaling pathways in which JNK1, RSK2, and MSK1 have a direct role in the regulation of Bad phosphorylation and its function.DISCUSSIONThe phosphorylation of Bad, a Bcl-2 family protein, may represent an important bridge between survival signaling by growth factor receptors and the prevention of apoptosis. Oncogenes involved in the signal transduction of growth factor receptors may mediate the requirement for extracellular stimuli to maintain protection from apoptosis, in part by increasing Bad phosphorylation. Therefore, identifying the specific signaling pathways involved in the regulation of Bad is crucial in our understanding of oncogenesis. In this study, we demonstrated that Bad is phosphorylated at serine 112, but not serine 136, early after UVB radiation. Furthermore, we found that UVB-induced serine 112 phosphorylation of Bad depends on MAP kinase signaling pathways in which JNK1 directly mediates serine 112 phosphorylation, whereas RSK2 and MSK1 transduce ERKs and p38 kinase signals by phosphorylating Bad.Exposure of cells to UV radiation elicits a complex set of acute cellular responses called “UV responses.” The initial signal triggering the UV response is in large part independent of DNA damage, but it instead appears to be mediated by a membrane-associated component of the Ras pathway and activation of MAP kinases (23Dhanasekaran N. Premkumar Reddy E. Oncogene. 1998; 17: 1447-1455Crossref PubMed Scopus (249) Google Scholar). ERKs are involved in survival signaling in response to a variety of growth factors (10Bonni A. Brunet A. West A.E. Datta S.R. Takasu M.A. Greenberg M.E. Science. 1999; 286: 1358-1362Crossref PubMed Scopus (1664) Google Scholar, 35Ip Y.T. Davis R.J. Curr. Opin. Cell Biol. 1998; 10: 205-219Crossref PubMed Scopus (1374) Google Scholar, 53Meier P. Evan G. Cell. 1998; 95: 295-298Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar), whereas activation of JNKs or p38 kinase is suggested to play decisive roles in the control of cell death (34Xia Z. Dickens M. Raingeaud J. Davis R.J. Greenberg M.E. Science. 1995; 270: 1326-1331Crossref PubMed Scopus (5027) Google Scholar). The early activation of JNKs and p38 kinase by tumor necrosis factor-α and overexpression of MAP kinase kinase 6, an upstream kinase of p38 kinase, also have been reported to contribute to survival signaling (36Roulston A. Reinhard C. Amiri P. Williams L.T. J. Biol. Chem. 1998; 273: 10232-10239Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar, 37Zechner D. Craig R. Hanford D.S. McDonough P.M. Sabbadini RA Glembotski C.C. J. Biol. Chem. 1998; 273: 8232-8239Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Our recent study demonstrates the requirement of JNK activation for tumor necrosis factor-α-induced JB6 cell transformation (44Huang C., Li, J.X., Ma, W.Y. Dong Z. J. Biol. Chem. 1999; 274: 29672-29676Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Embryos with disruption of Jnk1 andJnk2 genes exhibit increased apoptosis in the development of forebrain (54Kuan C.Y. Yang D.D. Samanta Roy D.R. Davis R.J. Rakic P. Flavell R.A. Neuron. 1999; 22: 667-676Abstract Full Text Full Text PDF PubMed Scopus (761) Google Scholar, 55Sabapathy K. Jochum W. Hochedlinger K. Chang L. Karin M. Wagner E.F. Mech. Dev. 1999; 89: 115-124Crossref PubMed Scopus (300) Google Scholar). In addition, integrin-mediated survival signaling has been shown to be mediated by the JNK pathway (56Almeida E.A. Ilic D. Han Q. Hauck C.R. Jin F. Kawakatsu H Schlaepfer D.D. Damsky C.H. J. Cell Biol. 2000; 149: 741-754Crossref PubMed Scopus (335) Google Scholar). However, little direct evidence has been obtained to show that the MAP kinase family regulates survival-signaling components in response to UV radiation. Very recently, we reported that ERK- and p38 kinase-dependent MSK1 activation, in addition to the phosphatidylinositol 3-kinase (PI3-K) pathway, is required for Akt activation early after UVB radiation (45Nomura M. Kaji A, Ma, W.Y. Zhong S. Liu G. Bowden G.T. Miyamoto K. Dong Z. J. Biol. Chem. 2001; 276: 25558-25567Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). In the present study, we further found that MAP kinases mediate UVB-induced Bad phosphorylation at serine 112. The results of our study indicated that JNK1 is a direct mediator of UVB-induced phosphorylation of Bad at serine 112 (Figs.3 B and 4 A). Although ERKs and p38 kinase did not directly phosphorylate Bad at serine 112, RSK2, a downstream kinase of ERKs (Fig. 4 B) (50Frodin M. Gammeltoft S. Mol. Cell. Endocrinol. 1999; 151: 65-77Crossref PubMed Scopus (614) Google Scholar), and MSK1, a downstream kinase of ERKs and p38 kinase (41Deak M. Clifton A.D. Lucocq L.M. Alessi D.R. EMBO J. 1998; 17: 4426-4441Crossref PubMed Scopus (842) Google Scholar, 45Nomura M. Kaji A, Ma, W.Y. Zhong S. Liu G. Bowden G.T. Miyamoto K. Dong Z. J. Biol. Chem. 2001; 276: 25558-25567Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 46Zhong S.P. Jansen C. She Q.B. Goto H. Inagaki M. Bode A.M., Ma, W.Y. Dong Z. J. Biol. Chem. 2001; 276: 33213-33219Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 51New L. Zhao M., Li, Y. Bassett W.W. Feng Y. Ludwig S. Padova F.D. Gram H. Han J. J. Biol. Chem. 1999; 274: 1026-1032Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar), were shown to be responsible for the phosphorylation in vitro and in vivo (Figs.Figure 4, Figure 5, Figure 6). Furthermore, the MAP kinase-dependent phosphorylation of Bad at serine 112 was found to be required for Bad dissociation from Bcl-XL (Fig. 7). Therefore, these data suggest a novel role for MAP kinases and their downstream kinases in the regulation of survival signal transduction pathways immediately following UV radiation. However, the significance of the members of MAP kinases being required for UVB-induced serine 112 phosphorylation of Bad and regulation of its function is not presently known. Some evidence indicates that cross-talk among ERKs, JNKs, and p38 kinase signaling may play an important role in determining cell survival and death (34Xia Z. Dickens M. Raingeaud J. Davis R.J. Greenberg M.E. Science. 1995; 270: 1326-1331Crossref PubMed Scopus (5027) Google Scholar, 57Canman C.E. Kastan M.D. Nature. 1996; 384: 213-214Crossref PubMed Scopus (173) Google Scholar). Further study will be required to confirm this hypothesis.UV-induced Bad phosphorylation at a single residue, serine 112, and activation of the PI3-K/Akt survival pathway have also recently been observed in human skin cells by Wan et al. (58Wan Y.S. Wang Z.Q. Shao Y. Voorhees J.J. Fisher G.J. Int. J. Oncol. 2001; 18: 461-466PubMed Google Scholar). They showed that the UV-induced serine 112 phosphorylation of Bad occurred in a PI3-K-dependent manner by using PI3-K inhibitors such as LY294002 and wortmannin. However, Akt, a downstream kinase of PI3-K, has been shown to catalyze the phosphorylation of Bad specifically at serine 136, but not serine 112 (8Datta S.R. Dudek H. Tao X. Masters S., Fu, H. Gotoh Y. Greenberg M.E. Cell. 1997; 91: 231-241Abstract Full Text Full Text PDF PubMed Scopus (4914) Google Scholar, 9del Peso L. Gonzalez-Garcia M. Page C. Herrera R. Nunez G. Science. 1997; 278: 687-689Crossref PubMed Scopus (1978) Google Scholar). Furthermore, previous studies have demonstrated the inhibitory effect of both LY294002 and wortmannin on ERK activation in several cell types after various modes of stimulation (59Hawes B.E. Luttrell L.M. van Biesen T. Lefkowitz R.J. J. Biol. Chem. 1996; 271: 12133-12136Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, 60Sutor S.L. Vroman B.T. Armstrong E.A. Abraham R.T. Karnitz L.M. J. Biol. Chem. 1999; 274: 7002-7010Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 61Wennstrom S. Downward J. Mol. Cell. Biol. 1999; 19: 4279-4288Crossref PubMed Scopus (254) Google Scholar). Our recent results also showed that pretreatment with LY294002 or overexpression of a dominant negative mutant of PI3-K subunit p85 blocks UVB-induced ERKs and MSK1 activation (45Nomura M. Kaji A, Ma, W.Y. Zhong S. Liu G. Bowden G.T. Miyamoto K. Dong Z. J. Biol. Chem. 2001; 276: 25558-25567Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar) as well as activation of RSK2 (data not shown), indicating the requirement for PI3-K upstream of ERKs following UVB radiation. The phosphorylation of Bad at serine 112 induced by UVB was also confirmed to be partially inhibited by pretreatment with 12.5–25 μm LY294002 in our experiments (data not shown). However, in light of the above findings and in context with our results here, inhibition of Bad serine 112 phosphorylation by LY294002 most likely occurs through inhibition of the ERKs/RSK2 and ERKs/MSK1 pathways, but not Akt.PKA has been shown to mediate IL-3-induced phosphorylation of Bad at serine 112 in a cAMP-dependent manner, offering an explanation for the survival-promoting effects of cAMP in some cell types (12Harada H. Becknell B. Wilm M. Mann M. Huang L.J. Taylor SS Scott J.D. Korsmeyer S.J. Mol. Cell. 1999; 3: 413-422Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar). However, recent studies have reported that the level of cAMP was not affected after stimulation with cytokines, suggesting that PKA activation by cAMP is not the principle means for Bad phosphorylation at serine 112 (62Scheid M.P. Foltz I.N. Young P.R. Schrader J.W. Duronio V. Blood. 1999; 93: 217-225Crossref PubMed Google Scholar, 63Scheid M.P. Schubert K.M. Duronio V. J. Biol. Chem. 1999; 274: 31108-31113Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar). Very recently, we showed that PKA was not activated following UVB radiation (46Zhong S.P. Jansen C. She Q.B. Goto H. Inagaki M. Bode A.M., Ma, W.Y. Dong Z. J. Biol. Chem. 2001; 276: 33213-33219Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Therefore, we conclude that PKA may not be involved in UVB-induced Bad phosphorylation at serine 112.Recently, α- and γ-PAK have also been shown to phosphorylate Bad at serine 112 in vitro and in vivo (13Schurmann A. Mooney A.F. Sanders L.C. Sells M.A. Wang H.G. Reed J.C. Bokoch G.M. Mol. Cell. Biol. 2000; 20: 453-461Crossref PubMed Scopus (305) Google Scholar, 14Jakobi R. Moertl E. Koeppel M.A. J. Biol. Chem. 2001; 276: 16624-16634Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Activation of α-PAK was shown to be induced by IL-3 in FL5.12 lymphoid progenitor cells (13Schurmann A. Mooney A.F. Sanders L.C. Sells M.A. Wang H.G. Reed J.C. Bokoch G.M. Mol. Cell. Biol. 2000; 20: 453-461Crossref PubMed Scopus (305) Google Scholar), but not by tumor necrosis factor-α (TNF-α) in BALB3T3 fibroblasts (14Jakobi R. Moertl E. Koeppel M.A. J. Biol. Chem. 2001; 276: 16624-16634Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). These results indicate that activation of α-PAK may depend on cell type differences or different extracellular stimuli. Furthermore, whether α-PAK is involved in IL-3-induced endogenous Bad phosphorylation at serine 112 has not been determined (13Schurmann A. Mooney A.F. Sanders L.C. Sells M.A. Wang H.G. Reed J.C. Bokoch G.M. Mol. Cell. Biol. 2000; 20: 453-461Crossref PubMed Scopus (305) Google Scholar). Overexpression of constitutively active γ-PAK stimulates cell survival of BALB3T3 fibroblasts in response to TNF-α, growth factor withdrawal, and UVC radiation (14Jakobi R. Moertl E. Koeppel M.A. J. Biol. Chem. 2001; 276: 16624-16634Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). The authors suggested that phosphorylation of Bad at serine 112 by γ-PAK may be one of the mechanisms for protection from cell death. However, whether UVC radiation induction of endogenous Bad phosphorylation and γ-PAK is required for the phosphorylation has not yet been investigated. Interestingly, expression of active γ-PAK increases the early activation of ERKs, JNKs, and p38 kinase induced by TNF-α (14Jakobi R. Moertl E. Koeppel M.A. J. Biol. Chem. 2001; 276: 16624-16634Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Currently, we are also identifying the upstream effectors of MAP kinases involved in UVB-induced phosphorylation of Bad at serine 112. Whether γ-PAK is one of the candidate effectors will need to be determined.A number of published works have suggested that serine 136 phosphorylation of Bad is physiologically important. Expression of a mutant Bad in which serine 136 was changed to alanine potentiates apoptosis, arguing that the inability of Akt to phosphorylate this altered residue promotes association with Bcl-XL, thus leading to cell death (7Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar, 8Datta S.R. Dudek H. Tao X. Masters S., Fu, H. Gotoh Y. Greenberg M.E. Cell. 1997; 91: 231-241Abstract Full Text Full Text PDF PubMed Scopus (4914) Google Scholar, 64Blume-Jensen P. Janknecht R. Hunter T. Curr. Biol. 1998; 8: 779-782Abstract Full Text Full Text PDF PubMed Google Scholar). However, singly phosphorylated Bad at serine 112 also proved incapable of binding to Bcl-XL (7Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar). Our studies here with endogenous Bad argue that Bad-Bcl-XLassociation is disrupted independently of serine 136 phosphorylation. Rather, the dissociation is primarily dependent upon the phosphorylation state of serine 112. The phosphorylation of Bad at serine 136 could not be detected following UVB radiation (Fig. 1). Furthermore, Bad was not shown to be phosphorylated at serine 136 by active MAP kinases (data not shown) and inhibition of MAP kinases did not result in activation of other protein kinases such as Akt (45Nomura M. Kaji A, Ma, W.Y. Zhong S. Liu G. Bowden G.T. Miyamoto K. Dong Z. J. Biol. Chem. 2001; 276: 25558-25567Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar) to phosphorylate Bad at serine 136 after UVB radiation (Fig. 7). On the other hand, loss of serine 112 phosphorylation of Bad, through inhibition of MAP kinases including ERKs, JNKs, and p38 kinase, completely restores the association of Bad with Bcl-XL(Fig. 7). Therefore, these results suggest that serine 136 may not necessarily be phosphorylated for cell survival in response to UVB radiation.In summary, our studies demonstrate that the phosphorylation of Bad at serine 112 induced by UVB radiation is mediated by the signaling of MAP kinases and their downstream kinases (Fig.8). In addition to serine 112 phosphorylation of Bad by RSK2 as demonstrated previously (10Bonni A. Brunet A. West A.E. Datta S.R. Takasu M.A. Greenberg M.E. Science. 1999; 286: 1358-1362Crossref PubMed Scopus (1664) Google Scholar, 11Tan Y. Ruan H. Demeter M.R. Comb M.J. J. Biol. Chem. 1999; 274: 34859-34867Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar), our results further identify JNK1 and MSK1 as novel and direct signal mediators of serine 112 phosphorylation in response to UVB radiation. The phosphorylation of Bad at serine 112 by MAP kinase-dependent pathways may cooperate with the PI3-K/Akt pathway (45Nomura M. Kaji A, Ma, W.Y. Zhong S. Liu G. Bowden G.T. Miyamoto K. Dong Z. J. Biol. Chem. 2001; 276: 25558-25567Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar) to balance UV-induced apoptotic signals, thereby preventing widespread cell death. Conversely, activation of these survival pathways by UV radiation may enhance inappropriate cell survival leading to skin cancer, as has been found in several other types of cancer (29Merienne K. Jacquot S. Zeniou M. Pannetier S. Sassone-Corsi P. Hanauer A. Oncogene. 2000; 19: 4221-4229Crossref PubMed Scopus (39) Google Scholar, 65Altiok S. Batt D. Altiok N. Papautsky A. Downward J. Roberts T.M. Avraham H. J. Biol. Chem. 1999; 274: 32274-32278Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Therefore, understanding the cascade of molecular signals in the UV-induced survival pathway may be helpful in designing therapeutic targets for prevention of skin cancer induced by UV radiation. The development and maintenance of healthy tissues is critically dependent on a balance between cell survival and cell death (apoptosis). Alterations of both pathways contribute to the clonal expansion of cancer cells. The Bcl-2 family of related proteins contains protein-protein interaction domains that facilitate homo- and heterodimerization. Some members, Bcl-2, Bcl-XL, Mcl-1, and A1, promote cell survival, whereas others, Bad, Bid, Bax, and Bak, promote cell death. A possible mechanism exists whereby the interactions resulting in homo- or heterodimerization of the various proteins define the fate of a cell (1Oltvai Z.N. Korsmeyer S.J. Cell. 1994; 79: 189-192Abstract Full Text PDF PubMed Scopus (773) Google Scholar, 2Reed J.C. Oncogene. 1998; 17: 3225-3236Crossref PubMed Scopus (936) Google Scholar). Bad, for example, has been shown to heterodimerize with Bcl-XL through interaction with its Bcl-2 homology 3 domain at the mitochondrial membrane (3Zha J. Harada H. Osipov K. Jockel J." @default.
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