Peltola Katriina J, Paukku Kirsi, Aho Teija L T, Ruuska Marja, Silvennoinen Olli, Koskinen Päivi J
Turku Centre for Biotechnology, University of Turku/Abo Akademi University, Turku, Finland.
Blood. 2004 May 15;103(10):3744-50. doi: 10.1182/blood-2003-09-3126. Epub 2004 Feb 5.
Signal transducer and activator of transcription 5 (STAT5) plays a critical role in cytokine-induced survival of hematopoietic cells. One of the STAT5 target genes is pim-1, which encodes an oncogenic serine/threonine kinase. Here we demonstrate that Pim-1 inhibits STAT5-dependent transcription in cells responsive to interleukin-3, prolactin, or erythropoietin. Ectopic expression of Pim-1 in cytokine-dependent FDCP1 myeloid cells results in reduced tyrosine phosphorylation and DNA binding of STAT5, indicating that Pim-1 interferes already with the initial steps of STAT5 activation. However, the Pim-1 kinase does not directly phosphorylate or bind to STAT5. By contrast, Pim-1 interacts with suppressor of cytokine signaling 1 (SOCS1) and SOCS3 and potentiates their inhibitory effects on STAT5, most likely via phosphorylation-mediated stabilization of the SOCS proteins. Thus, both Pim and SOCS family proteins may be components of a negative feedback mechanism that allows STAT5 to attenuate its own activity.
信号转导及转录激活因子5（STAT5）在细胞因子诱导的造血细胞存活中起关键作用。STAT5的靶基因之一是pim-1，其编码一种致癌性丝氨酸/苏氨酸激酶。在此我们证明，Pim-1在对白介素-3、催乳素或促红细胞生成素产生应答的细胞中抑制STAT5依赖性转录。在细胞因子依赖性FDCP1髓样细胞中异位表达Pim-1会导致STAT5的酪氨酸磷酸化和DNA结合减少，这表明Pim-1已经在干扰STAT5激活的初始步骤。然而，Pim-1激酶并不直接磷酸化或结合STAT5。相反，Pim-1与细胞因子信号转导抑制因子1（SOCS1）和SOCS3相互作用，并增强它们对STAT5的抑制作用，最有可能是通过磷酸化介导的SOCS蛋白稳定化。因此，Pim和SOCS家族蛋白可能都是负反馈机制的组成部分，该机制使STAT5能够减弱其自身活性。
