Heat shock protein 25 or inducible heat shock protein 70 activates heat shock factor 1: dephosphorylation on serine 307 through inhibition of ERK1/2 phosphorylation.
The expression of heat shock proteins (HSPs) is known to be increased via activation of heat shock factor 1 (HSF1), and excess expression of HSPs exerts feedback inhibition of HSF1. However, the molecular mechanism to modulate such relationships between HSPs and HSF1 is not clear. In the present study, we show that stable transfection of either Hsp25 or inducible Hsp70 (Hsp70i) increased expression of endogenous HSPs such as HSP25 and HSP70i through HSF1 activation. However, these phenomena were abolished when the dominant negative Hsf1 mutant was transfected to HSP25 or HSP70i overexpressed cells. Moreover, the increased HSF1 activity by either HSP25 or HSP70i was found to result from dephosphorylation of HSF1 on serine 307 that increased the stability of HSF1. Either HSP25 or HSP70i inhibited ERK1/2 phosphorylation because of increased MKP1 phosphorylation by direct interaction of these HSPs with MKP1. Treatment of HOS and NCI-H358 cells, which showed high expressions of endogenous HSF1, with small interfering RNA (siRNA) of either HSP27 (siHSP27)or HSP70i (siHSP70i) inhibited both HSP27 and HSP70i proteins; this was because of increased ERK1/2 phosphorylation and serine phosphorylation of HSF1. The results, therefore, suggested that when the HSF1 protein level was high in cancer cells, excess expression of HSP27 or HSP70i strongly facilitates the expression of HSP proteins through HSF1 activation, resulting in severe radio- or chemoresistance.
Seo
Haeng Ran
HR
Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706.
Chung
Da-Yeon
DY
Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706; Department of Food and Microbial Technology College of Natural Science, Seoul Women's University, Seoul 139-774.
Lee
Yoon-Jin
YJ
Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706.
Lee
Dae-Hoon
DH
Seegene Inc., Seoul 138-050.
Kim
Jong-Il
JI
Department of Food and Microbial Technology College of Natural Science, Seoul Women's University, Seoul 139-774.
Bae
Sangwoo
S
Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706.
Chung
Hee-Yong
HY
Department of Microbiology, College of Medicine, Hanyang University, Seoul 133-791.
Lee
Su-Jae
SJ
Laboratory of Radiation Experimental Therapeutics, Korea Institute of Radiological and Medical Sciences, Seoul 139-706.
Jeoung
Dooil
D
Division of Life Sciences, Kangwon National University College of Natural Sciences, Chuncheon 200-701, Korea.
Lee
Yun-Sil
YS
Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706. Electronic address: yslee@kcch.re.kr.
D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry*; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000737:chemistry*; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry*; D048052:Mitogen-Activated Protein Kinase 3 / Q000737:chemistry*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000737:chemistry*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine / Q000737:chemistry*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C057725:HSPB1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D012694:Serine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3