人类的核苷酸还原酶亚基hRRM2补充p53R2回应UV-induced在p53突变细胞中DNA修复。

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周B,刘X, X,雪L,达尔维什D,邱W, Shih J,胡EB, Luh F,日圆Y

人类的核苷酸还原酶亚基hRRM2补充p53R2回应UV-induced在p53突变细胞中DNA修复。

癌症研究》2003年10月15日,63 (20):6583 - 94。

PubMed ID

14583450 (在PubMed

]

文摘

核苷酸还原酶(RR)负责新创转换的核糖核苷二磷酸,脱氧核苷二磷酸,这对DNA合成和修复至关重要。RR由两个亚基组成,hRRM1 hRRM2。p53R2是一个新的RR家庭成员。因为绝大多数人类肿瘤具有突变型p53,重要的是要知道p53突变的分子机制调节RR和到什么程度。在这项研究中,我们调查的表达和功能p53R2和hRRM2在人类前列腺癌生物细胞紫外线处理后,具有与截断COOH-terminal p53突变,在人类的口咽癌KB细胞,具有野生型p53。p53R2(由免疫印迹分析和标准化相对于Coomassie中乐队)被抑制在生物细胞和紫外线照射后上调KB细胞。相比之下,hRRM2被紫外线差异在两种生物细胞和癌细胞。hRRM2和p53R2 mRNA水平被吸干,北部评估结果平行的免疫印迹。Coimmunoprecipitation化验使用agarose-conjugated山羊反人类的RRM1抗体证实p53R2绑定hRRM1在KB细胞在生物细胞减少,但增加紫外线治疗。hRRM2绑定hRRM1细胞株在相同条件下增加。 These results suggest that PC3 cells are deficient in both transcription of p53R2 and binding to hRRM1 in response to UV irradiation. Confocal microscopy further confirmed that these findings were not due to translocation of hRRM2 and p53R2 from the cytoplasm to the nucleus. RR activity was measured following UV treatment and shown to increase in PC3 cells. It was unchanged in proportional of KB cells. The RR activity is consistent with the expression of hRRM2 seen in the Western blots. Thus, we hypothesize that hRRM2 complements p53R2 to form RR holoenzyme and maintain RR activity in PC3 cells after UV treatment. To further confirm this hypothesis, we examined the effect of RRM2 inhibitors on cells exposed to UV. In PC3 cells, hydroxyurea inhibited hRRM2 and resulted in increased sensitivity to UV irradiation. We also examined the effect of UV treatment on the colony-forming ability of cells transfected with hRRM2 as well as p53R2 sense or antisense expression vectors. Expression of antisense hRRM2 in PC3 cells led to decreased hRRM2 expression and resulted in greater sensitivity to UV than observed in wild-type PC3 cells. Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3.

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药物靶点

药物	目标	类	生物	药理作用	行动
羟基脲	Ribonucleoside-diphosphate还原酶大亚基	蛋白质	人类	是的	抑制剂	细节

多肽

的名字	UniProt ID
Ribonucleoside-diphosphate还原酶亚基M2 B	Q7LG56	细节