Role of MAP kinases and their cross-talk in TGF-β1-induced... : Hepatology (original) (raw)

Role Of Map Kinases And Their Cross-Talk In Tgf-1-Induced Apoptosis In Fao Rat Hep-Atoma Cell Line: PDF Only

Role of MAP kinases and their cross-talk in TGF-β1-induced apoptosis in FaO rat hepatoma cell line

Park, Hyun-Jin1; Kim, Byung-Chul2; Kim, Seong-Jin2; Choi, Kyeong Sook*,1

1 Laboratory of Endocrinology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea

2 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD

*Address reprint requests to: Laboratory of Endocrinology, Institute for Medical Sciences, Ajou University Hospital Genomic Research Center for Gastroenterology, Ajou University School of Medicine, 5 Wonchon-Dong, Paldal-Gu, Suwon 442-749, Korea. fax: (82) 31-219-4503.

Received September 13, 2001; accepted February 27, 2002; previously published online December 30, 2003

Abstract

Transforming growth factor (TGF) β1 is a potent inducer of apoptosis in the liver. During TGF-β1-induced apoptosis, 3 mitogen-activated protein (MAP) kinases (extracellular signal-regulated kinase [ERK], c-Jun _N_-terminal kinase [JNK], and p38 kinase) showed simultaneously sustained activation in FaO rat hepatoma cells. TGF-β1-induced apoptosis was markedly enhanced when ERK activation was selectively inhibited by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059. In contrast, both interfering with p38 activity by overexpression of the dominant negative (DN) MKK6 mutant and inhibition of the JNK pathway by overexpression of the DN SEK1 mutant resulted in suppression of mitochondrial cytochrome c release, abrogating TGF-β1-induced apoptosis. In addition, antiapoptotic Bcl-2 blocked mitochondrial cytochrome c release, suppressing TGF-β1-induced activation of JNK and p38. Inhibition of ERK activity enhanced TGF-β1-induced p38 and JNK activation. However, inhibition of the JNK pathway suppressed p38 but induced transient ERK activation. Similarly, interfering with the p38 pathway also attenuated JNK activation but generated transient ERK activation in response to TGF-β1. These results indicate that disrupting one MAP kinase pathway affects the TGF-β1-induced activation of other MAP kinases, suggesting cross-talk among MAP kinase pathways. In conclusion, we propose that the balance and integration of MAP kinase signaling may regulate commitment to TGF-β1-induced apoptosis modulating the release of cytochrome c from mitochondria.