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-1 beta (IL-1 beta)-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.
Nishitai
Gen
G
Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Shimizu
Nao
N
Negishi
Takahiro
T
Kishimoto
Hiroyuki
H
Nakagawa
Kentaro
K
Kitagawa
Daiju
D
Watanabe
Tomomi
T
Momose
Haruka
H
Ohata
Shinya
S
Tanemura
Shuhei
S
Asaka
Satoshi
S
Kubota
Junko
J
Saito
Ryota
R
Yoshida
Hiroki
H
Mak
Tak W
TW
Wada
Teiji
T
Penninger
Josef M
JM
Azuma
Noriyuki
N
Nishina
Hiroshi
H
Katada
Toshiaki
T
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation; D006358:Hot Temperature; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics; D048688:MAP Kinase Kinase 7; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases