Paclitaxel (Taxol)-induced gene expression and cell death are both mediated by the activation of c-jun NH2-terminal kinase (JNK/SAPK)

被引:189
作者
Lee, LF
Li, GX
Templeton, DJ
Ting, JPY [1 ]
机构
[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA
[4] Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA
关键词
D O I
10.1074/jbc.273.43.28253
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Paclitaxel (Taxol) is a novel anti-cancer drug that has shown efficacy toward several malignant tumors, particularly ovarian tumors. We reported previously that paclitaxel can induce interleukin IL-8 promoter activation in subgroups of ovarian cancer through the activation of both AP-1 and nuclear factor kappa B. Further analysis of paclitaxel analogs indicates that the degree of IL-8 induction by analysis correlates with the extent of cell death; however, IL-8 itself is not the cause of cell death. This suggests that pathways that lead to IL-8 and cell death may overlap, although IL-8 per se does not kill tumor cells. To decipher the upstream signals for paclitaxel-induced transcriptional activation and cell death, we studied the involvement of protein kinases that lead to the activation of AP-1, specifically the c-Jun NH2-terminal kinase (JNK1), p38, and the extracellular signal-regulated kinase 1 (ERK1). The role of I kappa B in paclitaxel-induced cell death was also analyzed. Paclitaxel activated JNK, and to a lesser degree p38, but not ERK1. Paclitaxel-induced IL-8 promoter activation was inhibited by dominant-inhibitory mutants of JNK p38, and the super-repressor form of I kappa B alpha, but not by dominant-inhibitory forms of ERK1. Dominant-inhibitory mutants of JNK1 also greatly reduced paclitaxel-induced cell death, and the kinetics of JNK induction was closely followed by DNA fragmentation. These results indicate (i) that paclitaxel activates the JNK signaling pathway and (ii) that JNK activation is a common point of paclitaxel-induced gene induction and cell death.
引用
收藏
页码:28253 / 28260
页数:8
相关论文
共 72 条
[11]   Importance of acidic, proline/serine/threonine-rich, and GTP-binding regions in the major histocompatibility complex class II transactivator: Generation of transdominant-negative mutants [J].
Chin, KC ;
Li, GGX ;
Ting, JPY .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (06) :2501-2506
[12]   HOW MAP KINASES ARE REGULATED [J].
COBB, MH ;
GOLDSMITH, EJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (25) :14843-14846
[13]   Fas-induced proteolytic activation and intracellular redistribution of the stress-signaling kinase MEKK1 [J].
Deak, JC ;
Cross, JV ;
Lewis, M ;
Qian, YY ;
Parrott, LA ;
Distelhorst, CW ;
Templeton, DJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (10) :5595-5600
[14]   The novel receptor TRAIL-R4 induces NF-κB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain [J].
Degli-Esposti, MA ;
Dougall, WC ;
Smolak, PJ ;
Waugh, JY ;
Smith, CA ;
Goodwin, RG .
IMMUNITY, 1997, 7 (06) :813-820
[15]   JNK1 - A PROTEIN-KINASE STIMULATED BY UV-LIGHT AND HA-RAS THAT BINDS AND PHOSPHORYLATES THE C-JUN ACTIVATION DOMAIN [J].
DERIJARD, B ;
HIBI, M ;
WU, IH ;
BARRETT, T ;
SU, B ;
DENG, TL ;
KARIN, M ;
DAVIS, RJ .
CELL, 1994, 76 (06) :1025-1037
[16]   ACCURATE TRANSCRIPTION INITIATION BY RNA POLYMERASE-II IN A SOLUBLE EXTRACT FROM ISOLATED MAMMALIAN NUCLEI [J].
DIGNAM, JD ;
LEBOVITZ, RM ;
ROEDER, RG .
NUCLEIC ACIDS RESEARCH, 1983, 11 (05) :1475-1489
[17]   SHARED ACTIONS OF ENDOTOXIN AND TAXOL ON TNF RECEPTORS AND TNF RELEASE [J].
DING, AH ;
PORTEU, F ;
SANCHEZ, E ;
NATHAN, CF .
SCIENCE, 1990, 248 (4953) :370-372
[18]   ASSOCIATION OF SOS RAS EXCHANGE PROTEIN WITH GRB2 IS IMPLICATED IN TYROSINE KINASE SIGNAL TRANSDUCTION AND TRANSFORMATION [J].
EGAN, SE ;
GIDDINGS, BW ;
BROOKS, MW ;
BUDAY, L ;
SIZELAND, AM ;
WEINBERG, RA .
NATURE, 1993, 363 (6424) :45-51
[19]  
ETTINGER DS, 1993, J NATL CANC I MONOGR, V15, P177
[20]  
FORASTIERE AA, 1993, SEMIN ONCOL, V20, P56