Roscovitine inhibits STAT5 activity and induces apoptosis in the human leukemia virus type 1-transformed cell line MT-2.
Roscovitine inhibits STAT5 activity and induces apoptosis in the human leukemia virus type 1-transformed cell line MT-2.
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发表时间：
2003-12
期刊：
影响因子：
11.2
通讯作者：
S. Mohapatra;B. Chu;Sheng Wei;J. Djeu;P. Epling-Burnette;T. Loughran;R. Jove;W. J. Pledger
中科院分区：
文献类型：
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作者：
S. Mohapatra;B. Chu;Sheng Wei;J. Djeu;P. Epling-Burnette;T. Loughran;R. Jove;W. J. Pledger
表达人类白血病病毒(HTLV)1型的T细胞是成人T细胞白血病的病原体，对传统化疗具有显著的耐药性，显然需要有效杀死这些细胞的药物。在此，我们证明了细胞周期蛋白依赖性蛋白依赖性蛋白激酶(CDKs)的抑制剂罗斯科维汀可以诱导HTLV-1转化的T细胞系MT-2的凋亡。在caspase-3抑制剂存在或不存在的情况下，罗索维汀可阻止MT-2细胞酪氨酸磷酸化以及转录因子信号转导和转录激活剂(STAT)5的激活，并且在MT-2细胞中异位表达显性-阴性形式的STAT5可诱导细胞凋亡。在体内，罗索维汀和显性阴性的STAT5也降低了抗凋亡蛋白XIAP的表达，并且STAT5与XIAP启动子相关。抗血小板衍生生长因子(PDGF)α受体的抗体从未经处理但未经罗斯科维汀处理的细胞提取液中共沉淀STAT5。酪氨酸磷酸酶抑制剂原钒酸钠可阻断罗斯科维汀对STAT5/PDGFα受体相互作用、STAT5活性和细胞存活的抑制作用。我们认为，罗斯科维汀降低了酪氨酸磷酸化的PDGFα受体的丰度；结果，STAT5不会变得活跃，细胞生存所需的STAT5基因产物也不会表达。
T cells expressing human leukemia virus (HTLV) type 1, the etiological agent of adult T-cell leukemia, are remarkably resistant to conventional chemotherapy, and the need for drugs that effectively kill these cells is apparent. Here we show that roscovitine, an inhibitor of cyclin-dependent kinases (CDKs), induces the apoptosis of the HTLV-1-transformed T-cell line MT-2. Roscovitine prevented the tyrosine phosphorylation and consequent activation of the transcription factor signal transducer and activator of transcription (STAT) 5 when presented to MT-2 cells in the presence or absence of a caspase-3 inhibitor, and ectopic expression of a dominant-negative form of STAT5 in MT-2 cells induced apoptosis. Roscovitine and dominant-negative STAT5 also reduced the expression of the antiapoptotic protein XIAP, and STAT5 was associated with the XIAP promoter in vivo. Antibody to platelet-derived growth factor (PDGF) alpha receptors coprecipitated STAT5 from extracts of untreated but not roscovitine-treated cells. The tyrosine phosphatase inhibitor sodium orthovanadate ablated the inhibitory effects of roscovitine on STAT5/PDGF alpha receptor interaction, STAT5 activity, and cell survival. We suggest that roscovitine reduces the abundance of tyrosine-phosphorylated PDGF alpha receptors; as a result, STAT5 does not become active, and STAT5 gene products required for cell survival are not expressed.