Abstract |
AG957 is a tyrosine kinase antagonist which prior studies had shown inhibits p210bcr-abl tyrosine kinase activity and K562 chronic myelogenous leukemia cell growth. We report here the effects of AG957 on the physical state of p210bcr-abl and its signaling adapter molecules Shc and Grb2 in K562 cells. After exposure to AG957, the amount of tyrosine-phosphorylated native p210bcr-abl decreases, with the appearance of a high molecular weight (> 210 kDa) p210bcr-abl. This effect is seen after [32P] orthophosphate and [35S] methionine labeling. Material suggesting the involvement of p210bcr-abl in high molecular weight complexes also appears using anti-Shc, anti-Grb2 and anti- phosphotyrosine antibodies. AG957 also acts in vitro to shift native p210bcr-abl in anti-p210bcr-abl or anti-Grb2 immunoprecipitates to higher molecular weight forms under conditions where the drug can also act as an antagonist of p210bcr-abl autokinase activity. Incubation with dithiothreitol inhibits the appearance of > 210 kDa forms of p210bcr-abl in the in vitro reaction. These results leads to the hypothesis that AG957 does not act simply as a reversible tyrosine kinase antagonist, but can alter the normal amounts and physical associations of molecules important in tyrosine kinase signaling. These effects likely reflect covalent cross-links induced by the drug.
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Authors | G Kaur, E A Sausville |
Journal | Anti-cancer drugs
(Anticancer Drugs)
Vol. 7
Issue 8
Pg. 815-24
(Nov 1996)
ISSN: 0959-4973 [Print] England |
PMID | 8991184
(Publication Type: Journal Article)
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Chemical References |
- Antibodies, Monoclonal
- Benzylidene Compounds
- Nitriles
- Phosphorus Radioisotopes
- Sulfur Radioisotopes
- Tyrphostins
- tyrphostin AG957
- Fusion Proteins, bcr-abl
- Serine Endopeptidases
- glutamyl endopeptidase
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Topics |
- Animals
- Antibodies, Monoclonal
- Benzylidene Compounds
(pharmacology)
- Blotting, Western
- Cell Division
(drug effects)
- Fusion Proteins, bcr-abl
(chemistry, metabolism)
- Humans
- Hydrolysis
- Isotope Labeling
- Mice
- Molecular Weight
- Nitriles
(pharmacology)
- Phosphorus Radioisotopes
- Phosphorylation
- Precipitin Tests
- Serine Endopeptidases
- Signal Transduction
(drug effects)
- Sulfur Radioisotopes
- Tumor Cells, Cultured
- Tyrphostins
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