Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, Kitaoka T, Fukada T, Hibi M, Hirano T
Department of Molecular Oncology, Osaka University Medical School, Japan.
EMBO J. 1996 Jul 15;15(14):3651-8.
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.
白细胞介素-6（IL-6）可诱导多种细胞的分化或生长。关于这种细胞命运决定的分子基础，人们了解甚少。信号转导及转录激活蛋白（Stat）家族参与多种细胞因子和生长因子受体介导的信号传导，尽管它们的生物学作用尚未明确。为了探讨Stat蛋白在IL-6诱导的生长或分化过程中是否发挥作用，我们将两种以显性负性方式起作用的突变型Stat3导入M1白血病细胞，该细胞对IL-6的反应是生长停滞和终末分化。我们发现，显性负性形式的Stat3抑制了M1转化细胞中IL-6诱导的G(0)/G1期生长停滞以及巨噬细胞分化。Stat激活的阻断导致IL-6诱导的c-myb和c-myc表达抑制。此外，当Stat3被抑制时，IL-6主要通过缩短G1期的长度来促进M1细胞的生长。因此，IL-6同时产生生长促进信号以及生长停滞和分化诱导信号。Stat3可能是决定M1细胞从细胞生长到分化这一细胞命运的关键分子。
