Tissue inhibitor of metalloproteinase-1 promotes hematopoietic differentiation via caspase-3 upstream the MEKK1/MEK6/p38α pathway
Tissue inhibitor of metalloproteinase-1 promotes hematopoietic differentiation via caspase-3 upstream the MEKK1/MEK6/p38α pathway
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DOI：
10.1038/sj.leu.2404540
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发表时间：
2007-04-01
期刊：
影响因子：
11.4
通讯作者：
Petitfrere, E.
中科院分区：
文献类型：
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作者：
Dasse, E.;Bridoux, L.;Petitfrere, E.
TIMP-1除了具有基质金属蛋白酶抑制活性外，还具有其他生物学活性，如细胞存活和增殖。TIMP-1引起的细胞内信号通路开始阐明。我们以前已经表明，caspase-3和p38 a MAP激酶在TIMP-1诱导的UT-7细胞红系分化过程中被激活。在本研究中，我们证明了TIMP-1的分化作用可以扩展到IL-3依赖的髓系小鼠32 D细胞系和来自脐带血CD 34（+）细胞的人红系祖细胞。通过小干扰RNA转染和化学抑制剂的应用，我们证实了caspase-3参与了TIMP-1的分化作用。然后，我们确定MEKK 1激酶作为caspase-3底物，并证明MEKK 1/MEK 6/p38 α通路在TIMP-1诱导的造血分化中在caspase-3下游被激活。
Besides its matrix metalloproteinases inhibitory activity, TIMP-1 exhibits other biological activities such as cell survival and proliferation. The intracellular signalling pathway elicited by TIMP-1 begins to be elucidated. We have shown previously that the caspase-3 and the p38a MAP kinase were activated during TIMP-1-induced UT-7 cells erythroid differentiation. In this study, we demonstrated that TIMP-1 differentiating effect can be extended to the IL-3-dependent myeloid murine 32D cell line and human erythroid progenitors derived from cord blood CD34(+) cells. By performing small interfering RNA transfection and using chemical inhibitors, we evidenced that caspase-3 was involved in TIMP-1 differentiating effect. We then identified the MEKK1 kinase as a caspase-3 substrate and demonstrated that the MEKK1/MEK6/p38 alpha pathway was activated downstream the caspase-3 in TIMP-1-induced hematopoietic differentiation.