
PMID- 11278851
OWN - NLM
STAT- MEDLINE
DCOM- 20010726
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 276
IP  - 22
DP  - 2001 Jun 1
TI  - Paclitaxel induces prolonged activation of the Ras/MEK/ERK pathway independently 
      of activating the programmed cell death machinery.
PG  - 19555-64
AB  - Paclitaxel is a widely used chemotherapeutic agent and is known to induce 
      programmed cell death (apoptosis) in a variety of cell types, but the precise 
      underlying mechanisms are poorly understood. To elucidate these mechanisms, we 
      challenged human esophageal squamous cancer cell lines with paclitaxel and 
      investigated its effects upon signal transduction pathways. Physiologically 
      relevant concentrations of paclitaxel (1-1,000 nm) induced apoptosis. All three 
      mitogen-activated protein kinase (MAPK) family members, c-Jun N-terminal kinase 
      (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK) were activated 
      upon paclitaxel treatment. Interestingly, JNK activation and p38 MAPK activation 
      were delayed and peaked at 48 h, whereas ERK activity was sustained over 72 h. In 
      addition, Ras activation and MAPK/ERK kinase (MEK) phosphorylation were observed 
      in concordance with ERK activation. While ERK activation was completely ablated 
      by MEK inhibitors, immunoprecipitation and Western blot analysis revealed that 
      neither MEK-1 nor MEK-2 was involved, but instead another member of the MEK 
      family may potentially participate. Although pretreatment with a general caspase 
      inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone rescued the cell 
      death, it did not prevent Ras or ERK activation. Furthermore, inhibition of JNK, 
      p38 MAPK, or MEK did not alter PARP cleavage and the cell death induced by 
      paclitaxel. These results in aggregate suggest that the delayed activation of 
      JNK, p38 MAPK, and ERK was not linked to activation of the cell death machinery.
FAU - Okano J
AU  - Okano J
AD  - Division of Gastroenterology, Cancer Center, Department of Genetics, and Abramson 
      Family Cancer Research Institute, University of Pennsylvania, Philadelphia, 
      Pennsylvania 19104, USA.
FAU - Rustgi, A K
AU  - Rustgi AK
LA  - eng
GR  - P30 DK 50306/DK/NIDDK NIH HHS/United States
GR  - R01 DK57735/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20010305
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Protein Isoforms)
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.1.- (MAP2K2 protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 2)
RN  - EC 2.7.12.2 (MAP2K1 protein, human)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.4.22.- (CASP7 protein, human)
RN  - EC 3.4.22.- (Caspase 7)
RN  - EC 3.4.22.- (Caspases)
RN  - EC 3.6.5.2 (ras Proteins)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - Antineoplastic Agents, Phytogenic/*pharmacology
MH  - *Apoptosis
MH  - Blotting, Western
MH  - Caspase 7
MH  - Caspases/metabolism
MH  - Cell Nucleus/metabolism
MH  - Cell Survival
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation
MH  - Epidermal Growth Factor/pharmacology
MH  - Flow Cytometry
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases
MH  - MAP Kinase Kinase 1
MH  - MAP Kinase Kinase 2
MH  - MAP Kinase Signaling System
MH  - Mitogen-Activated Protein Kinase Kinases/*metabolism
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Models, Biological
MH  - Paclitaxel/*pharmacology
MH  - Phosphorylation
MH  - Precipitin Tests
MH  - Protein Isoforms
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Signal Transduction
MH  - Time Factors
MH  - Tumor Cells, Cultured
MH  - p38 Mitogen-Activated Protein Kinases
MH  - ras Proteins/*metabolism
EDAT- 2001/03/30 10:00
MHDA- 2001/07/28 10:01
CRDT- 2001/03/30 10:00
PHST- 2001/03/30 10:00 [pubmed]
PHST- 2001/07/28 10:01 [medline]
PHST- 2001/03/30 10:00 [entrez]
AID - S0021-9258(19)67100-0 [pii]
AID - 10.1074/jbc.M011164200 [doi]
PST - ppublish
SO  - J Biol Chem. 2001 Jun 1;276(22):19555-64. doi: 10.1074/jbc.M011164200. Epub 2001 
      Mar 5.
