UVA/B-induced apoptosis in human melanocytes involves translocation of cathepsins and Bcl-2 family members
UVA/B-induced apoptosis in human melanocytes involves translocation of cathepsins and Bcl-2 family members
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DOI：
10.1038/sj.jid.5700124
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发表时间：
2006-05-01
影响因子：
6.5
通讯作者：
Ollinger, Karin M.
中科院分区：
文献类型：
--
作者：
Bivik, Cecilia A.;Larsson, Petra K.;Ollinger, Karin M.
我们证明UVA/B通过线粒体途径诱导人黑素细胞凋亡，显示细胞色素c释放，半胱天冬酶-3激活和细胞核碎裂。死亡信号的结果取决于阳性和阴性凋亡调节因子之间的平衡，例如Bcl-2蛋白家族的成员。凋亡的黑素细胞，含有破碎的细胞核，表现出易位的促凋亡蛋白Bax和Bid从胞质溶胶到点状的神经管样结构。Bcl-2通常被认为只附着在细胞膜上，但它也存在于黑素细胞的胞浆中。在存活的黑素细胞部分中，即细胞核形态未改变的细胞中，抗凋亡蛋白Bcl-2和Bcl-XL在UVA/B后易位到线粒体。UVA/B暴露后，溶酶体蛋白酶，组织蛋白酶B和D，可能作为促凋亡介质，从溶酶体释放到胞质溶胶。通过显微注射组织蛋白酶B，诱导细胞核碎裂，证实了胞质组织蛋白酶的促凋亡作用。半胱氨酸或天冬氨酸组织蛋白酶抑制剂预处理后，黑素细胞Bax易位和凋亡显着减少。未检测到初始caspase-8活性，排除死亡受体途径的参与。总而言之，我们的研究结果强调了Bcl-2家族蛋白的易位具有紫外线诱导的黑素细胞凋亡的中央调节功能，并建议组织蛋白酶是Bax上游的促凋亡介质。
We demonstrate UVA/B to induce apoptosis in human melanocytes through the mitochondrial pathway, displaying cytochrome c release, caspase-3 activation, and fragmentation of nuclei. The outcome of a death signal depends on the balance between positive and negative apoptotic regulators, such as members of the Bcl-2 protein family. Apoptotic melanocytes, containing fragmented nucleus, show translocation of the proapoptotic proteins Bax and Bid from the cytosol to punctate mitochondrial-like structures. Bcl-2, generally thought to be attached only to membranes, was in melanocytes localized in the cytosol as well. In the fraction of surviving melanocytes, that is, cells with morphologically unchanged nucleus, the antiapoptotic proteins Bcl-2 and Bcl-XL were translocated to mitochondria following UVA/B. The lysosomal proteases, cathepsin B and D, which may act as proapoptotic mediators, were released from lysosomes to the cytosol after UVA/B exposure. Proapoptotic action of the cytosolic cathepsins was confirmed by microinjection of cathepsin B, which induced nuclear fragmentation. Bax translocation and apoptosis were markedly reduced in melanocytes after pretreatment with either cysteine or aspartic cathepsin inhibitors. No initial caspase-8 activity was detected, excluding involvement of the death receptor pathway. Altogether, our results emphasize translocation of Bcl-2 family proteins to have central regulatory functions of UV-induced apoptosis in melanocytes and suggest cathepsins to be proapoptotic mediators operating upstream of Bax.