Involvement of CD45 in DNA fragmentation in apoptosis induced by mitochondrial perturbing agents
Involvement of CD45 in DNA fragmentation in apoptosis induced by mitochondrial perturbing agents
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DOI：
10.1007/s10495-007-0162-9
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发表时间：
2008-02-01
期刊：
影响因子：
7.2
通讯作者：
Bernier, Jacques
中科院分区：
文献类型：
--
作者：
Desharnais, Philippe;Dupere-Minier, Genevieve;Bernier, Jacques
CD 45是具有磷酸酶活性的I型跨膜分子，其在有核造血细胞中占高达10%的细胞表面积。我们先前已经证明了在化学诱导的凋亡后，CD 45阴性T细胞中不存在核凋亡。本研究的目的是描述CD 45在细胞核凋亡中的作用。与野生型CD 45阳性T细胞相比，CD 45缺陷型T细胞系对三丁基锡（TBT）或H2 O2暴露后诱导的DNA片段化和染色质凝聚具有抗性，但对环己酰亚胺诱导的细胞凋亡没有抗性。CD 45转染缺陷细胞系导致TBT暴露后染色质凝聚和DNA片段化的恢复。在CD 45阳性和阴性T细胞系中，TBT暴露介导细胞内钙动员、半胱天冬酶-3活化和DFF 45裂解。此外，在p56 lck、ZAP-70和SHP-1表达缺陷的细胞中，TBT也诱导DNA断裂。亚细胞分配显示caspase-3和DFF 40的核定位减少。总之，这些结果首次证明，CD 45表达在细胞凋亡过程中的核小体间DNA片段化和染色质凝聚过程中起着关键作用。CD 45活性或其底物的活性似乎位于半胱天冬酶-3活化的下游，并在DFF 40在细胞核中的保留中起作用。
CD45 is a type I transmembrane molecule with phosphatase activity which comprises up to 10% of the cell surface area in nucleated haematopoietic cells. We have previously demonstrated the absence of nuclear apoptosis in CD45-negative T cells after chemical-induced apoptosis. The aim of this study was to characterize the role of CD45 in nuclear apoptosis. In contrast to wild type CD45-positive T cells, the CD45-deficient T cell lines are resistant to the induction of DNA fragmentation and chromatin condensation following tributyltin (TBT) or H2O2 exposure, but not to cycloheximide-induced apoptosis. CD45 transfection in deficient cell lines led to the restoration of chromatin condensation and DNA fragmentation following TBT exposure. In both CD45-positive and negative T cell lines, TBT exposure mediates intracellular calcium mobilization, caspase-3 activation and DFF45 cleavage. Moreover, DNA fragmentation was also induced by TBT in cells deficient in expression of p56lck, ZAP-70 and SHP-1. Subcellular partitioning showed a decrease in nuclear localisation of caspase-3 and DFF40. Together, these results demonstrate for the first time, that CD45 expression plays a key role in internucleosomal DNA fragmentation and chromatin condensation processes during apoptosis. CD45 activity or its substrates' activity, appears to be located downstream of caspase-3 activation and plays a role in retention of DFF40 in the nucleus.