p53-Independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-γ
p53-Independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-γ
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DOI：
10.1006/excr.2000.5073
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发表时间：
2001-01-15
影响因子：
3.7
通讯作者：
El-Deiry, WS
中科院分区：
文献类型：
--
作者：
Meng, RD;El-Deiry, WS
KILLER/DR 5是一种含有死亡结构域的促凋亡受体，可与细胞毒性配体TRAIL结合。最初报道DNA损伤后KILLER/DR 5 mRNA的诱导是p53依赖性的，但一些诱导凋亡的药物可以上调具有突变的p53的细胞系中KILLER/DR 5 mRNA的表达。我们进一步扩展了这些发现，通过分类的能力，各种骨化诱导药物，以增加KILLER/DR 5 mRNA的表达，在p53非依赖性的方式。拓扑异构酶抑制剂β-拉帕酮在具有野生型p53但不具有突变型p53的结肠癌细胞系中增加KILLER/DR 5 mRNA。与此相反，桦木酸，一种新的化疗化合物，诱导细胞凋亡和KILLER/DR 5 mRNA在黑色素瘤和胶质母细胞瘤细胞通过p53非依赖性机制。合成的糖皮质激素地塞米松在胶质母细胞瘤、卵巢癌和结肠癌细胞系中升高了KILLER/DR 5 mRNA，突变型p53经历凋亡，这种诱导被转录抑制剂放线菌素D抑制。尽管另一种糖皮质激素泼尼松龙也诱导细胞凋亡，但它不增加KILLER/DR 5 mRNA。最后，细胞因子干扰素-γ（IFN-γ）在具有突变型p53的细胞系中诱导细胞凋亡和KILLER/DR 5，并且在缺乏野生型STAT 1（一种与IFN-γ信号传导有关的转录因子）的细胞中，IFN-γ对KILLER/DR 5 mRNA的诱导被延迟。类似地，细胞因子TNF-α对KILLER/DR 5 mRNA的诱导在具有突变的STAT 1的细胞系中也被延迟。这些发现表明，KILLER/DR 5可能在特定药物诱导的p53非依赖性细胞凋亡中发挥作用，并值得进一步研究作为缺乏野生型p53的肿瘤化疗的新靶点。(C)北京：科学出版社.
KILLER/DR5 is a death-domain-containing proapoptotic receptor that binds to the cytotoxic Ligand TRAIL. It was originally reported that induction of KILLER/DR5 mRNA following DNA damage was p53-dependent, but some drugs that induce apoptosis can upregulate KILLER/DR5 mRNA expression in cell lines with mutated p53. We further extend those findings by classifying the capability of various apoptosis-inducing drugs to increase the expression of KILLER/DR5 mRNA in a p53-independent manner. beta -Lapachone, a topoisomerase inhibitor, increased KILLER/DR5 mRNA in colon cancer cell lines with wild-type p53 but not with mutant p53. In contrast, betulinic acid, a novel chemotherapeutic compound, induced apoptosis and KILLER/DR5 mRNA in melanoma and glioblastoma cells through a p53-independent mechanism. The synthetic glucocorticoid dexamethasone elevated KILLER/DR5 mRNA in glioblastoma, ovarian cancer, and colon cancer cell lines with mutant p53 undergoing apoptosis, and this induction was inhibited by the transcriptional inhibitor actinomycin D. Although another glucocorticoid, prednisolone, also induced apoptosis, it did not increase KILLER/DR5 mRNA Finally, the cytokine interferon-gamma (IFN-gamma) induced apoptosis and KILLER/DR5 in cell lines with mutant p53, and the induction of KILLER/DR5 mRNA by IFN-gamma was delayed in cells lacking wild-type STAT1, a transcription factor implicated in IFN-gamma signaling. Similarly, the induction of KILLER/DR5 mRNA by the cytokine TNF-alpha was also delayed in cell lines with mutated STAT1. These findings suggest that KILLER/DR5 may play a role in p53-independent apoptosis induced by specific drugs and warrants further investigation as a novel target for chemotherapy of tumors lacking wild-type p53. (C) 2001 Academic Press.