PMID- 10749863
OWN - NLM
STAT- MEDLINE
DCOM- 20000720
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 275
IP  - 23
DP  - 2000 Jun 9
TI  - Expression of oncogenic epidermal growth factor receptor family kinases induces 
      paclitaxel resistance and alters beta-tubulin isotype expression.
PG  - 17358-63
AB  - Oncogenic transformation confers resistance to chemotherapy through a variety of 
      mechanisms, including suppression of apoptosis, increased drug metabolism, and 
      modification of target proteins. Oncogenic epidermal growth factor receptor 
      family members, including EGFRvIII and HER2, are expressed in a broad spectrum of 
      human malignancies. Cell lines transfected with EGFRvIII and HER2 are more 
      resistant to paclitaxel-mediated cytotoxicity, and tubulin polymerization induced 
      by paclitaxel is suppressed compared with cells expressing wild type epidermal 
      growth factor receptor. Because differential expression of beta-tubulin isotypes 
      has been proposed to modulate paclitaxel resistance, we analyzed beta-tubulin 
      isotypes expressed in cell lines transfected with different oncogenes. EGFRvIII- 
      and HER2-expressing cells demonstrated equivalent total beta-tubulin protein 
      compared with cells transfected with wild type receptor or untransfected 
      controls. EGFRvIII-expressing cells demonstrated increases in class IVa 
      (2.5-fold) and IVb (3.1-fold) mRNA, and HER2-expressing cells showed increases in 
      class IVa (2. 95-fold) mRNA. Expression of oncogenic Ha-Ras did not change class 
      IV RNA levels significantly. Inhibition of EGFRvIII kinase activity using a 
      mutant allele with an inactivating mutation in the kinase domain decreased 
      expression of class IVa by 50% and partially reversed resistance to paclitaxel. 
      Expression of oncogenic epidermal growth factor receptor family members is 
      associated with modulation of both beta-tubulin isotype expression and paclitaxel 
      resistance in cells transformed by expression of the receptor. This effect on 
      tubulin expression may modulate drug resistance in human malignancies that 
      express these oncogenes.
FAU - Montgomery, R B
AU  - Montgomery RB
AD  - Department of Medicine and Oncology, Veterans Affairs Puget Sound Health Care 
      System, University of Washington, Seattle, Washington 98108, USA. 
      rbmontgo@u.washington.edu
FAU - Guzman, J
AU  - Guzman J
FAU - O'Rourke, D M
AU  - O'Rourke DM
FAU - Stahl, W L
AU  - Stahl WL
LA  - eng
GR  - CA60782/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Protein Isoforms)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tubulin)
RN  - 0 (epidermal growth factor receptor VIII)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - 3T3 Cells
MH  - Animals
MH  - Cell Transformation, Neoplastic
MH  - *Drug Resistance, Neoplasm
MH  - ErbB Receptors/*genetics/physiology
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Mice
MH  - Paclitaxel/*toxicity
MH  - Protein Isoforms/genetics
MH  - Receptor, ErbB-2/genetics/physiology
MH  - Recombinant Proteins/biosynthesis
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transfection
MH  - Tubulin/*genetics
EDAT- 2000/04/06 09:00
MHDA- 2000/07/25 11:00
CRDT- 2000/04/06 09:00
PHST- 2000/04/06 09:00 [pubmed]
PHST- 2000/07/25 11:00 [medline]
PHST- 2000/04/06 09:00 [entrez]
AID - S0021-9258(19)83250-7 [pii]
AID - 10.1074/jbc.M000966200 [doi]
PST - ppublish
SO  - J Biol Chem. 2000 Jun 9;275(23):17358-63. doi: 10.1074/jbc.M000966200.