Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway

被引:42
作者
Lee, YJ
Corry, PM
机构
[1] William Beaumont Hosp, Dept Radiat Oncol, Res Labs, Royal Oak, MI 48073 USA
[2] Seoul Natl Univ, Coll Nat Sci, Dept Mol Biol, Seoul, South Korea
[3] Seoul Natl Univ, Coll Nat Sci, Res Ctr Cell Differentiat, Seoul, South Korea
关键词
D O I
10.1023/A:1007059806016
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Although the synthesis of angiogenic factors in hypoxic regions of solid tumors is recognized as one of the critical steps in tumor growth and metastasis, the signal transduction pathway involved in hypoxic induction of basic fibroblast growth factor (bFGF) gene expression is still obscure. In the study described here, we investigated the intracellular responses to hypoxia and the mechanisms triggering the initiation of angiogenic activity in drug-resistant human breast carcinoma MCF-7/ADR cells. Northern blots showed an increase in the level of c-jun, c-fos, and bFGF mRNA during hypoxia. Gel mobility-shift analysis of nuclear extracts from hypoxia-exposed cells showed an increase in AP-1 binding activity. In addition, hypoxic treatment strongly activated c-Jun N-terminal kinase 1 (JNK1), leading to phosphorylation and activation of c-Jun. Expression of a dominant negative mutant of JNK1 suppressed hypoxia-induced JNK1 activation as well as bFGF gene expression. Taken together, hypoxia-induced bFGF gene expression is mediated through the stress-activated protein kinase (SAPK) signal transduction pathway.
引用
收藏
页码:1 / 8
页数:8
相关论文
共 54 条
[1]  
ABATE C, 1991, ONCOGENE, V6, P2179
[2]   ACTIVATING TRANSCRIPTION FACTOR-II DNA-BINDING ACTIVITY IS STIMULATED BY PHOSPHORYLATION CATALYZED BY P42 AND P54 MICROTUBULE-ASSOCIATED PROTEIN-KINASES [J].
ABDELHAFIZ, HA ;
HEASLEY, LE ;
KYRIAKIS, JM ;
AVRUCH, J ;
KROLL, DJ ;
JOHNSON, GL ;
HOEFFLER, JP .
MOLECULAR ENDOCRINOLOGY, 1992, 6 (12) :2079-2089
[3]   REQUIREMENT FOR INTEGRATION OF SIGNALS FROM 2 DISTINCT PHOSPHORYLATION PATHWAYS FOR ACTIVATION OF MAP KINASE [J].
ANDERSON, NG ;
MALLER, JL ;
TONKS, NK ;
STURGILL, TW .
NATURE, 1990, 343 (6259) :651-653
[4]   THE HEAT-SHOCK RESPONSE IN HELA-CELLS IS ACCOMPANIED BY ELEVATED EXPRESSION OF THE C-FOS PROTOONCOGENE [J].
ANDREWS, GK ;
HARDING, MA ;
CALVET, JP ;
ADAMSON, ED .
MOLECULAR AND CELLULAR BIOLOGY, 1987, 7 (10) :3452-3458
[5]   THE JUN PROTO-ONCOGENE IS POSITIVELY AUTOREGULATED BY ITS PRODUCT, JUN/AP-1 [J].
ANGEL, P ;
HATTORI, K ;
SMEAL, T ;
KARIN, M .
CELL, 1988, 55 (05) :875-885
[6]  
ANGEL P, 1985, CANCER CELL, V3, P315
[7]   HA-RAS AUGMENTS C-JUN ACTIVITY AND STIMULATES PHOSPHORYLATION OF ITS ACTIVATION DOMAIN [J].
BINETRUY, B ;
SMEAL, T ;
KARIN, M .
NATURE, 1991, 351 (6322) :122-127
[8]   ERKS - A FAMILY OF PROTEIN-SERINE THREONINE KINASES THAT ARE ACTIVATED AND TYROSINE PHOSPHORYLATED IN RESPONSE TO INSULIN AND NGF [J].
BOULTON, TG ;
NYE, SH ;
ROBBINS, DJ ;
IP, NY ;
RADZIEJEWSKA, E ;
MORGENBESSER, SD ;
DEPINHO, RA ;
PANAYOTATOS, N ;
COBB, MH ;
YANCOPOULOS, GD .
CELL, 1991, 65 (04) :663-675
[9]   ACTIVATION OF PROTEIN-KINASE-C DECREASES PHOSPHORYLATION OF C-JUN AT SITES THAT NEGATIVELY REGULATE ITS DNA-BINDING ACTIVITY [J].
BOYLE, WJ ;
SMEAL, T ;
DEFIZE, LHK ;
ANGEL, P ;
WOODGETT, JR ;
KARIN, M ;
HUNTER, T .
CELL, 1991, 64 (03) :573-584
[10]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3