Ubiquitin, SUMO‐1, and UCRP in Camptothecin Sensitivity and Resistance
Ubiquitin, SUMO‐1, and UCRP in Camptothecin Sensitivity and Resistance
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泛素、SUMO-1 和 UCRP 在喜树碱敏感性和耐药性中的作用
DOI：
10.1111/j.1749-6632.2000.tb07050.x
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发表时间：
2000
影响因子：
5.2
通讯作者：
Leroy F. Liu
中科院分区：
文献类型：
--
作者：
S. Desai;Y. Mao;Mei Sun;Tsai;Jiaxi Wu;Leroy F. Liu
在我们早期的研究中，我们观察到用抗癌药物喜树碱（CPT），拓扑异构酶I（topo I）处理的细胞迅速被26 S蛋白酶体多泛素化和破坏。最近，我们还报道了拓扑异构酶I与另一种泛素样蛋白SUMO-1（小泛素修饰物）结合，以响应CPT治疗。2在这里，我们报告了另一种泛素样蛋白在许多肿瘤细胞中的上调。在蛋白质印迹分析中，使用UCRP特异性抗血清将该蛋白质鉴定为干扰素诱导蛋白，称为ISG 15（干扰素刺激基因产物15）或UCRP（遍在蛋白交叉反应蛋白）。有趣的是，UCRP在用SV 40 T抗原转化的细胞系（2 RA）中显著升高，但在其未转化的亲本细胞系WI 38中没有，这表明UCRP的积累可能与致癌转化有关。我们还观察到一组结直肠癌和乳腺癌细胞系中CPT超敏反应和UCRP上调之间的相关性。相比之下，拓扑异构酶I的SUMO化在这些癌细胞系中没有显著差异。UCRP是一种15 kD的蛋白质，由两个结构域组成，每个结构域与泛素具有惊人的同源性。3这两个结构域通过在连接处插入额外的脯氨酸残基而相互连接。3发现其在干扰素治疗后被诱导。3该蛋白质的诱导与对病毒感染的抗性的出现相关。3有趣的是，UCRP在患有遗传性疾病共济失调毛细血管扩张症的人中组成性升高，这是NFκ B组成性激活的结果。4 SUMO-1也是一种15 kD蛋白，与泛素具有18%的序列相似性。5 1和UCRP以与泛素类似但不相同的方式与靶底物缀合。3，5充分证明了泛素缀合的底物被26 S蛋白酶体靶向破坏，5，但SUMO-1和UCRP与靶蛋白缀合的功能尚未被理解。已经提出SUMO-1缀合是细胞运输或拮抗泛素化以防止其靶破坏所需的。6在CPT治疗后SUMO-1缀合至topo I是否促进或防止其靶破坏。
In our earlier studies we observed that cells treated with the anticancer drug camptothecin (CPT), topoisomerase I (topo I), is rapidly multi-ubiquitinated and destroyed by 26S proteasome.1 Many tumor cells are found to be defective in this process. Recently, we have also reported that topoisomerase I is conjugated to another ubiquitin-like protein, SUMO-1 (small ubiquitin modifiers), in response to CPT treatment.2 Here we report upregulation of yet another ubiquitin-like protein in many tumor cells. This protein is identified as the interferon-inducible protein called ISG15 (interferon-stimulatory gene product 15) or UCRP (ubiquitin cross-reactive protein) using antiserum specific to UCRP in Western blot analysis. Interestingly, UCRP was greatly elevated in the cell line transformed with SV40 T-antigen (2RA), but not in its untransformed parental cell line, WI38, suggesting that accumulation of UCRP might be related to oncogenic transformation. We also observed a correlation between CPT hypersensitivity and UCRP upregulation in a panel of colorectal and breast cancer cell lines. By contrast, SUMOylation of topo I is not significantly different in these cancer cell lines. UCRP is a 15-kD protein and is composed of two domains, each of which bears striking homology to ubiquitin.3 These two domains are linked to each other with insertion of an extra proline residue at the junction.3 It was found to be induced upon interferon treatment.3 Induction of this protein is correlated with the appearance of resistance to viral infections.3 Interestingly, UCRP is constitutively elevated in humans with the inherited disease ataxia telangiectasia as a result of constitutive activation of NFκB.4 SUMO-1 is also a 15-kD protein and has an 18% sequence similarity to ubiquitin.5 Both SUMO-1 and UCRP are conjugated to target substrates in a way similar but not identical to that of ubiquitin.3,5 It is well demonstrated that ubiquitin-conjugated substrates are targeted for destruction by 26S proteasome,5 but the function of SUMO-1 and UCRP conjugation to the target protein has not yet been understood. It has been proposed that SUMO-1 conjugation is required for cellular trafficking or for antagonizing ubiquitination in order to prevent its target destruction.6 Whether SUMO-1 conjugation to topo I upon CPT treatment is to facilitate or to prevent its
DOI：
10.1073/pnas.080536597
发表时间：
2000-04-11
影响因子：
11.1
作者：
Mao, Y;Sun, M;Liu, LF
通讯作者：
Liu, LF