Stress Induces Mitochondria-mediated Apoptosis Independent of SAPK/JNK Activation in Embryonic Stem Cells

SAPK/JNK, which belongs to the family of mitogen-activated protein kinase (MAPK), is activated by many types of cellular stresses or extracellular signals and is involved in embryonic development, immune responses, and cell survival or apoptosis. However, the physiological roles of SAPK/JNK in the signaling of stress-induced apoptosis are still controversial. To evaluate the precise function, SAPK/JNK-inactivated mouse embryonic stem (ES) cells were generated by disrupting genes of the MAPK activators, SEK1 and MKK7. Although SAPK/JNK activation by various stresses was completely abolished in sek1–/– mkk7–/– ES cells, apoptotic responses including DNA fragmentation and caspase 3 activation still occurred normally, which displays a sharp contrast to apaf1–/– ES cells exhibiting profound defects in the mitochondria-dependent apoptosis. These normal apoptotic responses without SAPK/JNK activation were also observed in fibroblasts derived from sek1–/– mkk7–/– ES cells. Instead, interleukin-1β (IL-1β)-induced IL-6 gene expression was greatly suppressed in sek1–/– mkk7–/– fibroblasts. These results clearly show that SAPK/JNK activation is responsible for the inflammatory cytokine-induced gene expression but not essentially required for the mitochondria-dependent apoptosis at least in ES or fibroblast-like cells, which are prototypes of all cell lineages. SAPK/JNK, which belongs to the family of mitogen-activated protein kinase (MAPK), is activated by many types of cellular stresses or extracellular signals and is involved in embryonic development, immune responses, and cell survival or apoptosis. However, the physiological roles of SAPK/JNK in the signaling of stress-induced apoptosis are still controversial. To evaluate the precise function, SAPK/JNK-inactivated mouse embryonic stem (ES) cells were generated by disrupting genes of the MAPK activators, SEK1 and MKK7. Although SAPK/JNK activation by various stresses was completely abolished in sek1–/– mkk7–/– ES cells, apoptotic responses including DNA fragmentation and caspase 3 activation still occurred normally, which displays a sharp contrast to apaf1–/– ES cells exhibiting profound defects in the mitochondria-dependent apoptosis. These normal apoptotic responses without SAPK/JNK activation were also observed in fibroblasts derived from sek1–/– mkk7–/– ES cells. Instead, interleukin-1β (IL-1β)-induced IL-6 gene expression was greatly suppressed in sek1–/– mkk7–/– fibroblasts. These results clearly show that SAPK/JNK activation is responsible for the inflammatory cytokine-induced gene expression but not essentially required for the mitochondria-dependent apoptosis at least in ES or fibroblast-like cells, which are prototypes of all cell lineages. Apoptosis or programmed cell death is critical for many biological events such as embryonic development, immune responses, and tissue homeostasis in multicellular organisms. In mammalian cells, apoptotic signaling cascades can be divided into two broad categories: the intrinsic (mitochondria-dependent) and the extrinsic (death receptor-mediated) pathways. The initiation of mitochondria-dependent pathway requires a change in the organella membrane permeability that is prevented by anti-apoptotic molecules such as Bcl-2 and Bcl-XL and promoted by pro-apoptotic molecules including Bax and Bak, and the permeability change results in the release of mitochondrial proteins. One of the released proteins, cytochrome c, associates with Apaf1 and caspase 9 to activate the effector caspase 3 (1.Peng L. Deepak N. Imawati B. Srinivasa M.S. Manzoor A. Emad S.A. Xiaodong W. Cell. 1997; 91: 479-489Abstract Full Text Full Text PDF PubMed Scopus (6219) Google Scholar, 2.Orrenius S. Zhivotovsky B. Nicotera P. Nature Rev. Mol. Cell Biol. 2003; 4: 552-565Crossref PubMed Scopus (2406) Google Scholar). Cellular stresses such as UV irradiation and heat shock mediate apoptosis through the mitochondria-dependent pathway (3.Yoshida H. Kong Y.-Y. Yoshida R. Elia A.J. Hakem A. Hakem R. Penninger J.M. Mak T.W. Cell. 1998; 94: 739-750Abstract Full Text Full Text PDF PubMed Scopus (997) Google Scholar). However, upstream signaling that regulates the pro-apoptotic molecules remains to be elucidated. Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), 1The abbreviations used are: SAPK/JNK, stress-activated protein kinase/c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MKK, MAPK kinase; SEK, stress-activated protein kinase/extracellular signal-regulated kinase kinase; ES, embryonic stem; MEF, mouse embryonic fibroblast; IL, interleukin; TNF-α, tumor necrosis factor α; E, embryonic day; ERK, extracellular signal-regulated kinase.1The abbreviations used are: SAPK/JNK, stress-activated protein kinase/c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MKK, MAPK kinase; SEK, stress-activated protein kinase/extracellular signal-regulated kinase kinase; ES, embryonic stem; MEF, mouse embryonic fibroblast; IL, interleukin; TNF-α, tumor necrosis factor α; E, embryonic day; ERK, extracellular signal-regulated kinase. which belongs to the family of mitogen-activated protein kinase (MAPK), is activated not only by many types of cellular stresses including UV irradiation, heat shock, cisplatinum, etoposide, thapsigargin, and tunicamycin but also by inflammatory cytokines, interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α). The activated SAPK/JNK phosphorylates a number of substrates including the c-Jun component of the activator protein-1 transcription factor to regulate gene expression for the stress responses. Activation of SAPK/JNK requires the dual phosphorylation of Tyr and Thr residues located in a Thr-Pro-Tyr motif of the MAPK, and two kinases, SEK1 (also known as MKK4) and MKK7 (SEK2), are responsible for the phosphorylation (4.Davis R.J. Cell. 2000; 103: 239-252Abstract Full Text Full Text PDF PubMed Scopus (3633) Google Scholar, 5.Chang L. Karin M. Nature. 2001; 410: 37-40Crossref PubMed Scopus (4382) Google Scholar, 6.Manning A.M. Davis R.J. Nature Rev. Mol. Drug Disc. 2003; 2: 554-565Crossref PubMed Scopus (535) Google Scholar). SEK1 and MKK7 preferentially phosphorylate the Tyr and Thr residues of SAPK/JNK, respectively (7.Lawler S. Fleming Y. Goedert M. Cohen P. Curr. Biol. 1998; 8: 1387-1390Abstract Full Text Full Text PDF PubMed Google Scholar). Interestingly, the Tyr phosphorylation by SEK1 is sequentially followed by the Thr phosphorylation by MKK7 in stress-stimulated mouse embryonic stem (ES) cells (8.Wada T. Nakagawa K. Watanabe T. Nishitai G. Seo J. Kishimoto H. Kitagawa D. Sasaki T. Penninger J.M. Nishina H. Katada T. J. Biol. Chem. 2001; 276: 30892-30897Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 9.Kishimoto H. Nakagawa K. Watanabe T. Kitagawa D. Momose H. Seo J. Nishitai G. Shimizu N. Ohata S. Tanemura S. Asaka S. Goto T. Fukushi H. Yoshida H. Suzuki A. Sasaki T. Wada T. Penninger J.M. Nishina H. Katada T. J. Biol. Chem. 2003; 278: 16595-16601Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Targeted gene-disruption experiments in mice demonstrate that both SEK1 and MKK7 are required for embryonic development. Sek1–/– embryos die between embryonic day 10.5 (E10.5) and E12.5 with impaired liver formation and massive apoptosis (10.Ganiatsas S. Kwee L. Fujiwara Y. Perkins A. Ikeda T. Labow M.A. Zon L.I. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6881-6886Crossref PubMed Scopus (177) Google Scholar, 11.Nishina H. Vaz C. Billia P. Nghiem M. Sasaki T. Pompa J.L. Furlonger K. Paige C. Hui C.-C. Fischer K.D. Kishimoto H. Iwatsubo T. Katada T. Woodgett J.R. Penninger J.M. Development. 1999; 126: 505-516Crossref PubMed Google Scholar). We have recently shown that SEK1-mediated SAPK/JNK pathway downstream TNF-α receptor 1 participates in embryonic hepatoblast proliferation and survival via a pathway different from NF-κB-induced anti-apoptosis. On the other hand, mkk7–/– embryos die between E11.5 and 12.5 with similar defects in liver formation. These results indicate that SAPK/JNK activation mediated through SEK1 plus MKK7 plays indispensable roles in hepatoblast proliferation and survival during mouse embryogenesis (12.Watanabe T. Nakagawa K. Ohata S. Kitagawa D. Nishitai G. Seo J. Tanemura S. Shimizu N. Kishimoto H. Wada T. Aoki J. Arai H. Iwatsubo T. Mochita M. Watanabe T. Satake M. Ito Y. Matsuyama T. Mak T.W. Penninger J.M. Nishina H. Katada T. Dev. Biol. 2002; 250: 332-347Crossref PubMed Google Scholar). However, the physiological role of SAPK/JNK activation in cell survival and apoptosis is still controversial, being suggested to have an anti-apoptotic, pro-apoptotic, or no function in these processes (13.Lin A. BioEssays. 2002; 25: 17-24Crossref Scopus (369) Google Scholar). Mice lacking both JNK1 and JNK2 (Jnk1–/– Jnk2–/–) die around E11 with defective neural tube morphogenesis and altered apoptosis (14.Kuan C.-Y. Yang D.D. Roy D.R.S. Davis R.J. Rakic P. Flavell R.A. Neuron. 1999; 22: 667-676Abstract Full Text Full Text PDF PubMed Scopus (768) Google Scholar, 15.Sabapathy K. Jochum W. Hochedlinger K. Chang L. Karin M. Wagner E.F. Mech. Dev. 1999; 89: 115-124Crossref PubMed Scopus (301) Google Scholar). These results assign both pro- and anti-apoptotic functions to JNK1 and JNK2 in the development. It also appears that the SAPK/JNK pathway functions in a manner dependent on the types of cells and stimulus, and its different components can sometimes play opposing roles in apoptosis. The most convincing evidence to date that shows that the involvement of SAPK/JNK activation in pro-apoptotic function comes from Jnk1–/– Jnk2–/– and mkk4–/– mkk7–/– mouse embryonic fibroblasts (MEFs). Both Jnk1–/– Jnk2–/– and mkk4–/– mkk7–/– MEFs exhibited profound defects in stress-induced apoptosis (16.Tournier 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 (1540) Google Scholar, 17.Tournier C. Dong C. Turner T.K. Jones S.N. Flavell R.A. Davis R.J. Genes Dev. 2001; 15: 1419-1426Crossref PubMed Scopus (301) Google Scholar). Furthermore, it has been reported that active JNK causes the release of apoptogenic factors such as cytochrome c and Smac from isolated mitochondria in a cell-free system (18.Aoki H. Kang P.M. Hampe J. Yoshimura K. Noma T. Matsuzaki M. Izumo S. J. Biol. Chem. 2002; 277: 10244-10250Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar, 19.Chauhan D. Li G. Hideshima T. Podar K. Mitsiades C. Mitsiades N. Munshi N. Kharbanda S. Anderson K.C. J. Biol. Chem. 2003; 278: 17593-17596Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). These results strongly indicate that the SAPK/JNK activation directly regulates mitochondria-dependent apoptosis in pro-apoptotic direction. To evaluate the exact role of SAPK/JNK activation in mitochondria-dependent apoptosis, we here utilized mouse ES cells in terms of the following advantages. ES cells are a of all cell and can be into cells with ES cells not death including and TNF-α receptor 1 but have stress-induced mitochondria-dependent apoptotic The of SAPK/JNK activation is in ES cells. The results clearly show that SAPK/JNK activation is not required for the stress-induced mitochondria-dependent apoptosis in ES and cells. Instead, we that IL-6 gene expression was greatly impaired in derived from sek1–/– mkk7–/– ES cells. Cell and ES cell was in with and factor as H. Fischer K.D. L. A. Hakem R. A. Mak T.W. Woodgett J.R. Penninger J.M. Nature. 1997; PubMed Scopus Google Scholar). The of apaf1–/– ES cells was (3.Yoshida H. Kong Y.-Y. Yoshida R. Elia A.J. Hakem A. Hakem R. Penninger J.M. Mak T.W. Cell. 1998; 94: 739-750Abstract Full Text Full Text PDF PubMed Scopus (997) Google Scholar). Sek1–/– mkk7–/– ES cells were generated as in cells are from ES cells by with for without cells were at for and for and and Bax were from and were from heat shock protein was from and to and were in (8.Wada T. Nakagawa K. Watanabe T. Nishitai G. Seo J. Kishimoto H. Kitagawa D. Sasaki T. Penninger J.M. Nishina H. Katada T. J. Biol. Chem. 2001; 276: 30892-30897Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). and were from and was from DNA Y. G. Y. M. M. Sasaki T. S. PubMed Scopus Google Scholar). of ES Both SEK1 and and genes were as shown in 1 and were by a and respectively H. Fischer K.D. L. A. Hakem R. A. Mak T.W. Woodgett J.R. Penninger J.M. Nature. 1997; PubMed Scopus Google Scholar). 3 and were by a and an respectively H. Nakagawa K. Watanabe T. Kitagawa D. Momose H. Seo J. Nishitai G. Shimizu N. Ohata S. Tanemura S. Asaka S. Goto T. Fukushi H. Yoshida H. Suzuki A. Sasaki T. Wada T. Penninger J.M. Nishina H. Katada T. J. Biol. Chem. 2003; 278: 16595-16601Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, Y. G. Y. M. M. Sasaki T. S. PubMed Scopus Google Scholar). was by a as shown in of SAPK/JNK cells were at and for The cells were by tunicamycin UV UV and heat shock for SAPK/JNK were at for the The SAPK/JNK in the was with as an in in the of (8.Wada T. Nakagawa K. Watanabe T. Nishitai G. Seo J. Kishimoto H. Kitagawa D. Sasaki T. Penninger J.M. Nishina H. Katada T. J. Biol. Chem. 2001; 276: 30892-30897Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 9.Kishimoto H. Nakagawa K. Watanabe T. Kitagawa D. Momose H. Seo J. Nishitai G. Shimizu N. Ohata S. Tanemura S. Asaka S. Goto T. Fukushi H. Yoshida H. Suzuki A. Sasaki T. Wada T. Penninger J.M. Nishina H. Katada T. J. Biol. Chem. 2003; 278: 16595-16601Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The of the SAPK/JNK that been by with the was in a of the and cells were at in of a of and The cell were for and at for The were by and were to a membrane and with and The were by for the of a to the of cells were directly in and by followed by and SEK1 and MKK7 were with and and with and respectively (8.Wada T. Nakagawa K. Watanabe T. Nishitai G. Seo J. Kishimoto H. Kitagawa D. Sasaki T. Penninger J.M. Nishina H. Katada T. J. Biol. Chem. 2001; 276: 30892-30897Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 9.Kishimoto H. Nakagawa K. Watanabe T. Kitagawa D. Momose H. Seo J. Nishitai G. Shimizu N. Ohata S. Tanemura S. Asaka S. Goto T. Fukushi H. Yoshida H. Suzuki A. Sasaki T. Wada T. Penninger J.M. Nishina H. Katada T. J. Biol. Chem. 2003; 278: 16595-16601Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). DNA cells which been to and from were by of with and The cells were with and by the the cells were in of a of and at for at to and the cell were to and for DNA The DNA was in of and with for at The DNA were to on and by a UV D. Tanemura S. Ohata S. Shimizu N. Seo J. Nishitai G. Watanabe T. Nakagawa K. Kishimoto H. Wada T. T. T. Nishina H. Katada T. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). of 3 cells were as and with The cells, being in of a of and 1 were in and at The cell were at for 1 with in the of in and The was by of and to the release of was and at D. Tanemura S. Ohata S. Shimizu N. Seo J. Nishitai G. Watanabe T. Nakagawa K. Kishimoto H. Wada T. T. T. Nishina H. Katada T. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). cells were with and with at for 1 The cells were in a of and for at The apoptotic was by with Cell H. M. A.J. Fischer K.D. B. A. A. H. A. Mak T.W. Woodgett J.R. Penninger J.M. J. 1997; PubMed Scopus Google Scholar). cells were by cell and with The cells, being in of of 1 1 and were by a cells were at for at to cells, and mitochondria were to a tube and at for at were in of followed by at for at and in The were by and was with the and mitochondrial heat shock protein was from ES cells by by and to a IL-6 and were by the DNA The to mouse IL-6 and were the following and and and of the experiments were at least with different of the cell and the results were most of the shown are of Apoptosis through in ES the on apoptosis in ES cells, which cells stress by the of heat a that and by mitochondria-dependent apoptosis by directly with Apaf1 and cytochrome c and the of a K. D.D. A. T. P. Cohen Cell Biol. 2000; 2: PubMed Scopus Google Scholar, A. L. Cell Biol. 2000; 2: PubMed Scopus Google Scholar, C. P. L. S.A. C. S. G. C. Cell Biol. 2000; 2: PubMed Scopus Google Scholar). shown in various stresses DNA formation and caspase 3 which was by in ES cells. However, these apoptotic responses were by the To the involvement of Apaf1 in the stress-induced apoptosis, ES cells lacking Apaf1 (3.Yoshida H. Kong Y.-Y. Yoshida R. Elia A.J. Hakem A. Hakem R. Penninger J.M. Mak T.W. Cell. 1998; 94: 739-750Abstract Full Text Full Text PDF PubMed Scopus (997) Google were to the shown in apoptosis in to various stresses including heat shock, cisplatinum, etoposide, thapsigargin, and tunicamycin was completely in apaf1–/– ES cells. These results clearly show that the stress-induced apoptosis is mediated through mitochondria in ES cells. SAPK/JNK Activation in ES both and the role of SAPK/JNK activation in the stress-induced and mitochondria-dependent apoptosis, ES cells lacking both and MKK7 were of the we a and and genes as H. Nakagawa K. Watanabe T. Kitagawa D. Momose H. Seo J. Nishitai G. Shimizu N. Ohata S. Tanemura S. Asaka S. Goto T. Fukushi H. Yoshida H. Suzuki A. Sasaki T. Wada T. Penninger J.M. Nishina H. Katada T. J. Biol. Chem. 2003; 278: 16595-16601Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, H. Fischer K.D. L. A. Hakem R. A. Mak T.W. Woodgett J.R. Penninger J.M. Nature. 1997; PubMed Scopus Google Scholar). The generated both SEK1 and MKK7 completely and these are used as sek1–/– mkk7–/– ES cells in shown in not only stress-induced activation but also the of SAPK/JNK was completely in sek1–/– mkk7–/– ES cells. Apoptosis in sek1–/– mkk7–/– ES the various apoptotic responses including caspase 3 DNA and were in sek1–/– mkk7–/– ES cells in with and apaf1–/– ES cells the apoptotic responses were still observed clearly in sek1–/– mkk7–/– ES cells at the as ES cells. In sharp such responses were completely abolished in apaf1–/– cells. The and of apoptosis were also the between sek1–/– mkk7–/– and ES cells and not the SAPK/JNK appears to no on the stress-induced apoptosis in ES cells. of Activation in Apoptosis in sek1–/– mkk7–/– ES it has been reported that MAPK, plays a pro-apoptotic role M. J. Davis R.J. Science. PubMed Scopus Google we the of a on UV stress-induced apoptosis. shown in suppressed the phosphorylation of but to the stress-induced apoptosis both in and sek1–/– mkk7–/– ES cells. These results indicate that activation is not responsible for the stress-induced apoptosis in ES cells. of SAPK/JNK Activation for Bax in ES results shown in 3 that SAPK/JNK activation is not required for mitochondria-dependent apoptosis in ES cells. We the initiation of mitochondria-dependent apoptosis, the of Bax from to mitochondrial it has been recently reported that SAPK/JNK activation apoptosis in cells S. S. K. B. S. R.J. A. Neuron. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). shows the of the Bax in to UV irradiation in sek1–/– and ES cells. were no the types of ES cells. These results clearly show that SAPK/JNK activation is not required for the initiation of mitochondria-dependent apoptosis in ES cells. Apoptosis in sek1–/– mkk7–/– it has recently been reported that SAPK/JNK is for stress-induced apoptosis in (16.Tournier 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 (1540) Google Scholar, 17.Tournier C. Dong C. Turner T.K. Jones S.N. Flavell R.A. Davis R.J. Genes Dev. 2001; 15: 1419-1426Crossref PubMed Scopus (301) Google ES cells were with and to into cells. shown in stress-induced apoptosis by DNA fragmentation was also observed at the between sek1–/– mkk7–/– and cells as been observed in ES cells These results indicate that SAPK/JNK not its on the stress-induced apoptosis in cells as as in ES cells. IL-6 in sek1–/– mkk7–/– the physiological role of SAPK/JNK activation in ES or cells, we gene expression by an inflammatory shown in IL-6 was at 1 and in cells. However, was greatly in sek1–/– mkk7–/– cells, which Furthermore, the IL-6 expression was greatly suppressed by the JNK in cells SAPK/JNK activation appears to play an role in the inflammatory cytokine-induced gene expression the apoptotic responses at least in ES or cells. In the we have reported that sek1–/– are to and apoptosis and that apoptosis is in sek1–/– H. Vaz C. Billia P. Nghiem M. Sasaki T. Pompa J.L. Furlonger K. Paige C. Hui C.-C. Fischer K.D. Kishimoto H. Iwatsubo T. Katada T. Woodgett J.R. Penninger J.M. Development. 1999; 126: 505-516Crossref PubMed Google Scholar, H. Fischer K.D. L. A. Hakem R. A. Mak T.W. Woodgett J.R. Penninger J.M. Nature. 1997; PubMed Scopus Google Scholar). These results indicate that SAPK/JNK activation is involved in cell However, it has been reported that Jnk1–/– Jnk2–/– and mkk4–/– mkk7–/– MEFs are to apoptosis (16.Tournier 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 (1540) Google Scholar, 17.Tournier C. Dong C. Turner T.K. Jones S.N. Flavell R.A. Davis R.J. Genes Dev. 2001; 15: 1419-1426Crossref PubMed Scopus (301) Google Scholar). Furthermore, are many other the involvement of SAPK/JNK activation both in cell survival and in apoptosis. the role of SAPK/JNK in cell survival and apoptosis is still (13.Lin A. BioEssays. 2002; 25: 17-24Crossref Scopus (369) Google Scholar). results not the that activation is required for the stress-induced and mitochondria-dependent (4.Davis R.J. Cell. 2000; 103: 239-252Abstract Full Text Full Text PDF PubMed Scopus (3633) Google Scholar, 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 (1540) Google Scholar, 17.Tournier C. Dong C. Turner T.K. Jones S.N. Flavell R.A. Davis R.J. Genes Dev. 2001; 15: 1419-1426Crossref PubMed Scopus (301) Google at least in ES and cells, on the following SAPK/JNK activation is completely dependent on the of both SEK1 and MKK7 in mouse ES cells in which stress-induced apoptosis is mediated through mitochondria The sek1–/– mkk7–/– ES cells a in the SAPK/JNK activation in to a of but normal stress-induced apoptosis as the as cells MAPK, was not involved in the stress-induced apoptosis Bax was of into mitochondrial in to UV irradiation in sek1–/– mkk7–/– ES cells as observed in the cells the apoptosis in to various stresses such as etoposide, and occurred in sek1–/– mkk7–/– cells. be a signaling that is required for the initiation of stress-induced apoptosis in ES and cells. To the involvement of MKK7 in cell and we have recently mkk7–/– MEFs from mouse Interestingly, and mkk7–/– MEFs and of cell death in to UV at of cellular mkk7–/– MEFs a to the apoptosis. N. M. T. M. K. T. H. and J. M. for These results suggested that the to UV observed in Jnk1–/– Jnk2–/– and mkk4–/– mkk7–/– MEFs (16.Tournier 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 (1540) Google Scholar, 17.Tournier C. Dong C. Turner T.K. Jones S.N. Flavell R.A. Davis R.J. Genes Dev. 2001; 15: 1419-1426Crossref PubMed Scopus (301) Google have to cellular SAPK/JNK activation is for hepatoblast proliferation (12.Watanabe T. Nakagawa K. Ohata S. Kitagawa D. Nishitai G. Seo J. Tanemura S. Shimizu N. Kishimoto H. Wada T. Aoki J. Arai H. Iwatsubo T. Mochita M. Watanabe T. Satake M. Ito Y. Matsuyama T. Mak T.W. Penninger J.M. Nishina H. Katada T. Dev. Biol. 2002; 250: 332-347Crossref PubMed Google the MEFs the of in cell and in to stress-induced apoptosis to impaired it be to of JNK1 plus JNK2 in Jnk1–/– Jnk2–/– or plus MKK7 in mkk4–/– mkk7–/– MEFs can the apoptotic to UV However, with Jnk1–/– Jnk2–/– mice clearly show that SAPK/JNK activation is required not only for but also for in the of mouse (14.Kuan C.-Y. Yang D.D. Roy D.R.S. Davis R.J. Rakic P. Flavell R.A. Neuron. 1999; 22: 667-676Abstract Full Text Full Text PDF PubMed Scopus (768) Google Scholar, 15.Sabapathy K. Jochum W. Hochedlinger K. Chang L. Karin M. Wagner E.F. Mech. Dev. 1999; 89: 115-124Crossref PubMed Scopus (301) Google Scholar). was a of cell death in the of to neural tube In was apoptosis and caspase activation in the in Jnk1–/– Jnk2–/– mouse SAPK/JNK activation plays a pro-apoptotic role SAPK/JNK activation be involved in apoptosis SAPK/JNK is activated in cells by with and and regulates the of factor and cell proliferation B. M. T. Karin M. Y. Cell. Full Text PDF PubMed Scopus Google Scholar). we reported impaired and proliferation in sek1–/– H. M. A.J. Fischer K.D. B. A. A. H. A. Mak T.W. Woodgett J.R. Penninger J.M. J. 1997; PubMed Scopus Google Scholar). It has recently been reported that activation of cells in the of different of a of and cell proliferation D. T. N. L. J. Hess P. Flavell R.A. Davis R.J. M. J. 2002; PubMed Scopus Google Scholar). SAPK/JNK activation plays an role in cell is a in and the of gene expression for It has been reported that SAPK/JNK activation is required for the gene expression of a IL-6 and a in a cell by of a or of A. H. S. R. M. K. J. M. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. S. A. A. M. R. A. J. K. K. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). These results indicate that activation of SAPK/JNK the phosphorylation of a family of of activator in the gene expression of IL-6 and In we have also observed the impaired IL-6 gene expression both in sek1–/– mkk7–/– cells and in cells These results the between SAPK/JNK activation and IL-6 gene expression cells and also indicate that SAPK/JNK activation a and for immune responses. the SAPK/JNK regulates cell proliferation and gene expression in embryonic and immune responses stress-induced apoptosis. We and for with We also R. Woodgett for and

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