Involvement of c-Src kinase in the regulation of TGF-beta1-induced apoptosis.
Transforming growth factor-beta1 (TGF-beta1) is a potent inducer of apoptosis in normal hepatocytes, and acquiring resistance to TGF-beta1 may be a critical step in the development of hepatocellular carcinoma (HCC). In this study, we investigated the possible involvement of c-Src in the regulation of TGF-beta1-induced apoptosis. TGF-beta1 induced transient activation of c-Src and its subsequent caspase-mediated degradation concomitant with cell death in FaO hepatoma cells, which are sensitive to TGF-beta1. In response to TGF-beta1, activated c-Src was translocated into the cytoplasmic membrane, then relocated to the nuclei of apoptotic cells during its cleavage. In TGF-beta1-induced apoptotic cells, c-Src maintained its tight association with p85 FAK fragment cleaved by caspases, possibly contributing to focal adhesion disassembly. TGF-beta1-induced apoptosis was enhanced by either inhibition of c-Src activity using PP1 or PP2, or by overexpression of dominant-negative c-Src. In contrast, overexpression of constitutively active c-Src inhibited apoptosis suppressing TGF-beta1-induced activation of p38, JNK and caspases. In many HCC cell lines resistant to TGF-beta1, enhanced c-Src activity was detected. We hypothesize that activated c-Src in HCC may contribute to resistance against the apoptotic and/ or antiproliferative properties of TGF-beta1.
Park
Seok Soon
SS
Institute for Medical Sciences, Ajou University School of Medicine, 5 Wonchon-Dong, Paldal-Gu, Suwon 442-749, Korea.
Eom
Young-Woo
YW
Kim
Eun Hee
EH
Lee
Ji Hyun
JH
Min
Do Sik
DS
Kim
Sungsub
S
Kim
Seong-Jin
SJ
Choi
Kyeong Sook
KS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D000081247:CSK Tyrosine-Protein Kinase; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D051899:Smad2 Protein; D051900:Smad3 Protein; D013347:Subcellular Fractions / Q000201:enzymology; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D019061:src-Family Kinases
D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D020169:Caspases