STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity.
Activating mutations of c-kit at codon 816 (Asp(816)) have been identified in variety of malignancies, including acute myeloid leukemia (AML), mastocytosis and germ cell tumors. The mutant c-Kit receptor confers cytokine independence and induces tumorigenicity. However, the molecular mechanisms, particularly the changes in the signal transduction pathways, responsible for these biological effects induced by mutant c-Kit are largely undefined. Using the human embryonic kidney cell line, 293, we show in the current report that constitutive activation of STAT3 and STAT1 is associated with D816H mutant c-Kit. Transfection of dominant negative STAT3, but not STAT1 inhibits mutant c-Kit mediated anchorage-independent growth in vitro and tumor formation in vivo. Expression of constitutively activated STAT3 restores the mutant c-Kit receptor's transforming ability in 293 cells. These results demonstrate that activation of STAT3 by Asp(816) mutant c-Kit is required for the anchorage-independent growth and tumorigenicity induced by Asp(816) mutant c-Kit.
Ning
Z Q
ZQ
Division of Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Li
J
J
McGuinness
M
M
Arceci
R J
RJ
D019943:Amino Acid Substitution; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects / Q000637:transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D003062:Codon / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D019281:Dimerization; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D009857:Oncogenes; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection
D003062:Codon; D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D019089:Stem Cell Factor; D015534:Trans-Activators; D019009:Proto-Oncogene Proteins c-kit