STAT5 activation contributes to growth and viability in Bcr/Abl-transformed cells.
The transcription factor STAT5 is constitutively tyrosine phosphorylated and activated after transformation of hematopoietic cells by p210Bcr/Abl. A truncated form of STAT5B (triangle upSTAT5; aa, 1-683) that lacks tyrosine 699 and the transcriptional activation domain was introduced into Ba/F3p210 cells under the control of a tetracycline-inducible promoter. Treatment of these cells with doxycycline, a tetracycline analogue, induced expression of triangle upSTAT5 and inhibited STAT5-dependent transcription. triangle upSTAT5 coprecipitated with STAT5 and decreased Bcr/Abl-dependent tyrosine phosphorylation of endogenous STAT5. Induction of triangle upSTAT5 inhibited growth of Ba/F3p210 cells (26%-52% of control levels at 4 days) but did not cause cell-cycle arrest. triangle upSTAT5 reduced viability of Ba/F3p210 cells and increased sensitivity of the cells to the cytotoxic drugs hydroxyurea and cytarabine. These results indicate that high-level expression of triangle upSTAT5, as achieved here by using a tetracycline-inducible promoter, inhibits STAT5 activity, reduces the growth rate of Ba/F3p210 cells by inhibiting viability, and results in increased sensitivity to chemotherapeutic drugs. It is therefore likely that STAT5 activation plays a role in the transformation of hematopoietic cell lines by p210Bcr/Abl. (Blood. 2000;95:2118-2125)
Sillaber
C
C
Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Gesbert
F
F
Frank
D A
DA
Sattler
M
M
Griffin
J D
JD
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival; D003561:Cytarabine / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D017930:Genes, Reporter; D006918:Hydroxyurea / Q000494:pharmacology; D051379:Mice; D008894:Milk Proteins; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050799:STAT5 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D003561:Cytarabine; D014443:Tyrosine; D016044:Fusion Proteins, bcr-abl; D004318:Doxycycline; D006918:Hydroxyurea