A Central Role for Stat3 in IL-6-induced Regulation of Growth and Differentiation in M1 Leukemia Cells

EMBO J. 1996 Jul 15;15(14):3651-8.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Base Sequence
  • Binding Sites
  • Cell Differentiation / physiology*
  • Cell Division / physiology*
  • Cytokine Receptor gp130
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • G1 Phase
  • Humans
  • Interleukin-6 / physiology*
  • Leukemia, Myeloid, Acute
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myb
  • Proto-Oncogene Proteins c-myc / metabolism
  • STAT3 Transcription Factor
  • Sequence Deletion
  • Signal Transduction*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • DNA-Binding Proteins
  • IL6ST protein, human
  • Il6st protein, mouse
  • Interleukin-6
  • Membrane Glycoproteins
  • Oligodeoxyribonucleotides
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myb
  • Proto-Oncogene Proteins c-myc
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Trans-Activators
  • Cytokine Receptor gp130