Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1.
Heat shock protein 72 (Hsp72) is thought to protect cells against cellular stress. The protective role of Hsp72 was investigated by determining the effect of this protein on the stress-activated protein kinase signaling pathways. Prior exposure of NIH 3T3 cells to mild heat shock (43 degrees C for 20 min) resulted in inhibition of H(2)O(2)-induced activation of apoptosis signal-regulating kinase 1 (ASK1). Overexpression of Hsp72 also inhibited H(2)O(2)-induced activation of ASK1 as well as that of downstream kinases in the p38 mitogen-activated protein kinase (MAPK) signaling cascade. Recombinant Hsp72 bound directly to ASK1 and inhibited ASK1 activity in vitro. Furthermore, coimmunoprecipitation analysis revealed a physical interaction between endogenous Hsp72 and ASK1 in NIH 3T3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ASK1 and ASK1-dependent apoptosis. Hsp72 antisense oligonucleotides prevented the inhibitory effects of mild heat shock on H(2)O(2)-induced ASK1 activation and apoptosis. These observations suggest that Hsp72 functions as an endogenous inhibitor of ASK1.
Park
Hee-Sae
HS
National Creative Research Initiative Center for Cell Death. Graduate School of Biotechnology, Korea University, Seoul 136-701, South Korea.
Cho
Ssang-Goo
SG
Kim
Chang Kyun
CK
Hwang
Hyun Sub
HS
Noh
Kyung Tae
KT
Kim
Mi-Sung
MS
Huh
Sung-Ho
SH
Kim
Myung Jin
MJ
Ryoo
Kanghyun
K
Kim
Eun Kyung
EK
Kang
Woo Jin
WJ
Lee
Jae-Seon
JS
Seo
Jeong-Sun
JS
Ko
Young-Gyu
YG
Kim
Sunghoon
S
Choi
Eui-Ju
EJ
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004789:Enzyme Activation; D017930:Genes, Reporter; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D016376:Oligonucleotides, Antisense; D016877:Oxidants; D011993:Recombinant Fusion Proteins; D006861:Hydrogen Peroxide; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse