A constitutively active Lck kinase promotes cell proliferation and resistance to apoptosis through signal transducer and activator of transcription 5b activation
A constitutively active Lck kinase promotes cell proliferation and resistance to apoptosis through signal transducer and activator of transcription 5b activation
复制标题
DOI：
10.1158/1541-7786.mcr-05-0202
复制
发表时间：
2006-01-01
影响因子：
5.2
通讯作者：
Yu, CL
中科院分区：
文献类型：
--
作者：
Shi, MJ;Cooper, JC;Yu, CL
Lck是Src家族蛋白酪氨酸激酶，主要在T细胞中表达。Lck激酶的异常表达或激活在淋巴和非淋巴恶性肿瘤中都有报道。然而，lck介导的肿瘤发生机制在很大程度上仍不清楚。在这篇报道中，我们建立了一个四环素诱导的系统来研究具有负调控酪氨酸点突变的组成活性Lck突变体的生化和生物学效应。活性Lck激酶的表达可诱导酪氨酸磷酸化和转录信号换能器5b （STAT5b）的dna结合活性，STAT5b是STAT家族成员，在多种肿瘤细胞中被激活。活跃的Lck激酶与细胞中的STAT5b相互作用，表明Lck可能直接使STAT5b磷酸化。在白介素-3 （IL-3）依赖的BaF3细胞中表达组成型活性Lck突变体可促进细胞增殖。此外，活跃的Lck激酶保护BaF3细胞免受IL-3戒断诱导的凋亡死亡，并导致不依赖IL-3的生长。外源性野生型STAT5b的表达可以进一步增强致癌Lck激酶的这些转化特性，但STAT5b的显性阴性形式会减弱这种转化特性。总之，我们的结果表明STAT5b可能参与lck介导的细胞转化。
Lck is a Src family protein tyrosine kinase and is expressed predominantly in T cells. Aberrant expression or activation of Lck kinase has been reported in both lymphoid and nonlymphoid malignancies. However, the mechanisms underlying Lck-mediated oncogenesis remain largely unclear. In this report, we establish a tetracycline-inducible system to study the biochemical and biological effects of a constitutively active Lck mutant with a point mutation at the negative regulatory tyrosine. Expression of the active Lck kinase induces both tyrosine phosphorylation and DNA-binding activity of signal transducer and activator of transcription 5b (STAT5b), a STAT family member activated in a variety of tumor cells. The active Lck kinase interacts with STAT5b in cells, suggesting that Lck may directly phosphorylate STAT5b. Expression of the constitutively active Lck mutant in interleukin-3 (IL-3)-dependent BaF3 cells promotes cell proliferation. In addition, the active Lck kinase protects BaF3 cells from IL-3 withdrawal-induced apoptotic death and leads to IL-3-independent growth. These transforming properties of the oncogenic Lck kinase can be further augmented by expression of exogenous wild-type STAT5b but attenuated by a dominant-negative form of STAT5b. All together, our results suggest the potential involvement of STAT5b in Lck-mediated cellular transformation.