Deregulation of AP-1 proteins in collagen gel-induced epithelial cell apoptosis mediated by low substratum rigidity.
In this study, we established that collagen gel, but not collagen gel coating, induced apoptosis exclusively in epithelial cell lines, which indicated that low substratum rigidity might trigger cell apoptosis. To confirm this, we used collagen gels with different rigidities due to cross-linking or physical disruption of collagen fibrils caused by sonication. We found that collagen gel-induced apoptosis was inversely correlated with substratum rigidity. Low substratum rigidity collagen gel-induced apoptosis was neither prevented by Bcl-2 overexpression nor preceded by mitochondrial release of cytochrome c. This suggested that the mitochondrial pathway was not involved in low substratum rigidity-induced apoptosis. Low substratum rigidity activated c-Jun N-terminal kinase (JNK) within 4 h, but it also rapidly down-regulated c-Jun within 1 h and triggered persistent aberrant expression of c-Fos for at least 24 h. Either reduced c-Jun expression or c-Fos overexpression induced apoptosis in several epithelial cells. Inhibiting low substratum rigidity-induced JNK activation prevented aberrant c-Fos expression but only partially blocked low substratum rigidity-induced apoptosis. Taking these results together, we conclude that low substratum rigidity collagen gel induced apoptosis in epithelial cells and that deregulated AP-1 proteins mediated that apoptosis, at least in part.
Wang
Yao-Hsien
YH
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
Chiu
Wen-Tai
WT
Wang
Yang-Kao
YK
Wu
Ching-Chou
CC
Chen
Tsu-Ling
TL
Teng
Chiao-Feng
CF
Chang
Wen-Tsan
WT
Chang
Hsien-Chang
HC
Tang
Ming-Jer
MJ
D000818:Animals; D017209:Apoptosis; D006690:Bisbenzimidazole / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003094:Collagen / Q000737:chemistry*; D045304:Cytochromes c / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000737:chemistry*
D019253:Proto-Oncogene Proteins c-bcl-2; D018808:Transcription Factor AP-1; D003094:Collagen; D045304:Cytochromes c; D006690:Bisbenzimidazole