Kawai Taro, Akira Shizuo, Reed John C
The Burnham Institute, La Jolla, California 92037, USA.
Mol Cell Biol. 2003 Sep;23(17):6174-86. doi: 10.1128/MCB.23.17.6174-6186.2003.
PML oncogenic domains (PODs), also referred to as nuclear dot 10 bodies, Kreb's bodies, or nuclear bodies, represent nuclear structures implicated in the regulation of a variety of cellular processes, including transcription, tumor suppression, and apoptosis. ZIP kinase (ZIPK) is a proapoptotic protein kinase with homology to DAP kinase, a protein kinase implicated in apoptosis. We show here that ZIPK is present in PODs, where it colocalizes with and binds to proapoptotic protein Daxx. Arsenic trioxide (As(2)O(3)) and gamma interferon (IFN-gamma), which accentuate POD formation, increased the association of ZIPK with PODs. In contrast, the kinase-inactive ZIPK resides in nuclei with a diffuse pattern and significantly prevents the association of Daxx with PODs, implying that ZIPK recruits Daxx to PODs via its catalytic activity. ZIPK also binds and phosphorylates proapoptotic protein Par-4. Association of ZIPK with Daxx was enhanced by coexpression of Par-4. Activation of caspases and induction of apoptosis were also observed in cells overexpressing these proteins. Conversely, small-interfering RNA-mediated reduction of ZIPK, Daxx, or Par-4 expression decreased activation of caspase and apoptosis induced by As(2)O(3) and IFN-gamma. These results suggest that ZIPK, in collaboration with Daxx and Par-4, mediates a novel nuclear pathway for apoptosis.
早幼粒细胞白血病致癌结构域（PODs），也被称为核点10体、克雷布斯体或核体，是与多种细胞过程调节相关的核结构，这些过程包括转录、肿瘤抑制和细胞凋亡。ZIP激酶（ZIPK）是一种与DAP激酶具有同源性的促凋亡蛋白激酶，DAP激酶是一种与细胞凋亡有关的蛋白激酶。我们在此表明，ZIPK存在于PODs中，在那里它与促凋亡蛋白Daxx共定位并结合。三氧化二砷（As(2)O(3)）和γ干扰素（IFN-γ）可增强POD形成，增加ZIPK与PODs的关联。相反，激酶失活的ZIPK以弥散模式存在于细胞核中，并显著阻止Daxx与PODs的关联，这意味着ZIPK通过其催化活性将Daxx招募到PODs中。ZIPK还结合并磷酸化促凋亡蛋白Par-4。Par-4的共表达增强了ZIPK与Daxx的关联。在过表达这些蛋白的细胞中也观察到了半胱天冬酶的激活和细胞凋亡的诱导。相反，小干扰RNA介导的ZIPK、Daxx或Par-4表达的降低减少了由As(2)O(3)和IFN-γ诱导的半胱天冬酶激活和细胞凋亡。这些结果表明，ZIPK与Daxx和Par-4协同作用，介导了一条新的细胞凋亡核途径。
