TUMOR SUPPRESSOR FUNCTION OF THE INTERFERON-INDUCED DOUBLE-STRANDED RNA-ACTIVATED PROTEIN-KINASE
TUMOR SUPPRESSOR FUNCTION OF THE INTERFERON-INDUCED DOUBLE-STRANDED RNA-ACTIVATED PROTEIN-KINASE
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DOI：
10.1073/pnas.90.1.232
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发表时间：
1993-01-01
影响因子：
11.1
通讯作者：
HOVANESSIAN, AG
中科院分区：
文献类型：
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作者：
MEURS, EF;GALABRU, J;HOVANESSIAN, AG
RNA依赖蛋白激酶在人类细胞中是一种M(R)68,000蛋白(p68激酶)，在小鼠细胞中是一种M(R)65,000蛋白(p65激酶)。P65/P68是一种由干扰素诱导的丝氨酸/苏氨酸激酶，通常由双链RNA激活。一旦被激活，该激酶的已知功能是通过真核细胞起始因子2的磷酸化来抑制蛋白质的合成。在这里，我们研究了表达人p68激酶的小鼠NIH 3T3克隆在小鼠中的致瘤性，无论是野生型还是突变的失活激酶，在催化结构域II的不变赖氨酸-296上进行了单一氨基酸替换。突变的p68激酶的表达与恶性转化表型相关，导致在所有接种的小鼠中在7-12天内产生直径至少1厘米的大肿瘤。相比之下，在接种了表达野生型重组p68激酶或仅表达内源性p65激酶的NIH3T3细胞克隆的小鼠中，几周内没有观察到肿瘤生长。这些结果表明，功能性p65/p68激酶(新近称为PKR)，通过一种仍未明确的机制，也可能起到肿瘤抑制作用。因此，干扰素抑制肿瘤生长的途径之一可能是通过其诱导该激酶表达增强的能力。
RNA-dependent protein kinase is a M(r) 68,000 protein in human cells (p68 kinase) or a M(r) 65,000 protein in murine cells (p65 kinase). p65/p68 is a serine/threonine kinase induced by interferon treatment and generally activated by double-stranded RNAs. Once activated, the known function of this kinase is inhibition of protein synthesis through phosphorylation of the eukaryotic initiation factor 2. Here we have investigated the potential for tumorigenicity in mice of murine NIH 3T3 clones expressing human p68 kinase, either the wild-type or a mutant inactive kinase with a single amino acid substitution in the invariant lysine-296 in the catalytic domain II. Expression of the mutant p68 kinase was correlated with a malignant transformation phenotype, giving rise to the production of large tumors of at least 1 cm in diameter within 7-12 days in all inoculated mice. In contrast, no tumor growth was observed for several weeks in mice inoculated with NIH 3T3 cell clones expressing either the wild-type recombinant p68 kinase or only the endogenous p65 kinase, the murine analogue of the p68 kinase. These results suggest that functional p65/p68 kinase (recently called PKR), by a still undefined mechanism, may also act as a tumor suppressor. Consequently, one of the pathways by which interferon inhibits tumor growth might be through its capacity to induce the enhanced expression of this kinase.