A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells.
Interleukin-6 (IL-6) induces either differentiation or growth of a variety of cells. Little is known about the molecular basis of this cellular decision. The family of signal transducer and activator of transcription (Stat) proteins are involved in signaling through a variety of cytokine and growth factor receptors, although their biological roles have not been established. To address whether Stat proteins play roles in IL-6-induced growth or differentiation, we introduced two types of mutant Stat3 acting in a dominant-negative manner into M1 leukemic cells which respond to IL-6 with growth arrest and terminal differentiation. We show that dominant-negative forms of Stat3 inhibited both IL-6-induced growth arrest at G(0)/G1 and macrophage differentiation in the M1 transformants. Blocking of Stat activation resulted in inhibition of IL-6-induced repression of c-myb and c-myc. Furthermore, IL-6 enhanced the growth of M1 cells primarily through shortening the length of the G1 period when Stat3 was suppressed. Thus IL-6 generates both growth-enhancing signals and growth arrest- and differentiation-inducing signals at the same time. Stat3 may be a key molecule which determines the cellular decision from cell growth to differentiation in M1 cells.
Nakajima
K
K
Department of Molecular Oncology, Osaka University Medical School, Japan.
Yamanaka
Y
Y
Nakae
K
K
Kojima
H
H
Ichiba
M
M
Kiuchi
N
N
Kitaoka
T
T
Fukada
T
T
Hibi
M
M
Hirano
T
T
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016193:G1 Phase; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050796:STAT3 Transcription Factor; D017384:Sequence Deletion; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130