PMID- 9927194
OWN - NLM
STAT- MEDLINE
DCOM- 19990216
LR  - 20151119
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 18
IP  - 2
DP  - 1999 Jan 14
TI  - Differential regulation of mitogen-activated protein kinases by 
      microtubule-binding agents in human breast cancer cells.
PG  - 377-84
AB  - Drug design targeted at microtubules has led to the advent of some potent 
      anti-cancer drugs. In the present study, we demonstrated that microtubule-binding 
      agents (MBAs) taxol and colchicine induced immediate early gene (c-jun and ATF3) 
      expression, cell cycle arrest, and apoptosis in the human breast cancer cell line 
      MCF-7. To elucidate the signal transduction pathways that mediate such biological 
      activities of MBAs, we studied the involvement of mitogen-activated protein (MAP) 
      kinases. Treatment with taxol, colchicine, or other MBAs (vincristine, 
      podophyllotoxin, nocodazole) stimulated the activity of c-jun N-terminal kinase 1 
      (JNK1) in MCF-7 cells. In contrast, p38 was activated only by taxol and none of 
      the MBAs changed the activity of extracellular signal-regulated protein kinase 2 
      (ERK2). Activation of JNK1 or p38 by MBAs occurred subsequent to the 
      morphological changes in the microtubule cytoskeleton induced by these compounds. 
      Furthermore, baccatine III and beta-lumicolchicine, inactive analogs of taxol and 
      colchicine, respectively, did not activate JNKI or p38. These results suggest 
      that interactions between microtubules and MBAs are essential for the activation 
      of these kinases. Pretreatment with the antioxidants N-acetyl-L-cysteine (NAC), 
      ascorbic acid or vitamin E, blocked H2O2- or doxorubicin-induced JNKI activity, 
      but had no effect on JNKI activation by MBAs, excluding a role for oxidative 
      stress. However, BAPTA/AM, a specific intracellular Ca2+ chelator, attenuated 
      JNK1 activation by taxol but not by colchicine, and had no effect on microtubule 
      changes induced by taxol. Thus, stabilization or depolymerization of microtubules 
      may regulate JNK1 activity via distinct downstream signaling pathways. The 
      differential activation of MAP kinases opens up a new avenue for addressing the 
      mechanism of action of antimicrotubule drugs.
FAU - Shtil, A A
AU  - Shtil AA
AD  - Department of Molecular Genetics, College of Medicine, University of Illinois at 
      Chicago 60607, USA.
FAU - Mandlekar, S
AU  - Mandlekar S
FAU - Yu, R
AU  - Yu R
FAU - Walter, R J
AU  - Walter RJ
FAU - Hagen, K
AU  - Hagen K
FAU - Tan, T H
AU  - Tan TH
FAU - Roninson, I B
AU  - Roninson IB
FAU - Kong, A N
AU  - Kong AN
LA  - eng
GR  - R01-AI38649/AI/NIAID NIH HHS/United States
GR  - R01-ES06887/ES/NIEHS NIH HHS/United States
GR  - R37CA40333/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 139890-68-9 (1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid 
      acetoxymethyl ester)
RN  - 526U7A2651 (Egtazic Acid)
RN  - 5J49Q6B70F (Vincristine)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - L36H50F353 (Podophyllotoxin)
RN  - P88XT4IS4D (Paclitaxel)
RN  - SH1WY3R615 (Nocodazole)
RN  - SML2Y3J35T (Colchicine)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Breast Neoplasms/*metabolism/pathology
MH  - Calcium/metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Cell Cycle/drug effects
MH  - Colchicine/pharmacology
MH  - Egtazic Acid/analogs & derivatives/pharmacology
MH  - Enzyme Activation
MH  - Humans
MH  - Microtubules/*drug effects/metabolism
MH  - Nocodazole/pharmacology
MH  - Paclitaxel/pharmacology
MH  - Podophyllotoxin/pharmacology
MH  - Tumor Cells, Cultured
MH  - Vincristine/pharmacology
EDAT- 1999/02/02 00:00
MHDA- 1999/02/02 00:01
CRDT- 1999/02/02 00:00
PHST- 1999/02/02 00:00 [pubmed]
PHST- 1999/02/02 00:01 [medline]
PHST- 1999/02/02 00:00 [entrez]
AID - 10.1038/sj.onc.1202305 [doi]
PST - ppublish
SO  - Oncogene. 1999 Jan 14;18(2):377-84. doi: 10.1038/sj.onc.1202305.