The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments
The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments
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DOI：
10.1073/pnas.94.24.13181
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发表时间：
1997-11-25
影响因子：
11.1
通讯作者：
Wright, JA
中科院分区：
文献类型：
--
作者：
Fan, HZ;Huang, AP;Wright, JA
我们最近的研究表明，核糖核苷酸还原酶的限速组分R2的不受调控的表达，通过与活化的癌基因合作，增强了转化和恶性潜能。我们现在证明，核糖核苷酸还原酶的R1组分具有肿瘤抑制活性。导致软琼脂中菌落形成效率显著降低，锚定独立性降低，体内恶性潜能明显抑制。在三种ras转化细胞系中，R1过表达导致致瘤性消失或明显抑制，此外，过表达R1的细胞形成肺转移的能力降低了约85%。在高恶性小鼠10T1/2衍生的RMP-6细胞系中也观察到转移抑制活性，该细胞系由致癌I as， myc和突变p53组合转化。此外，与R1过表达细胞相比，将R1反义序列和致癌ras共转染的NIH 3T3细胞的锚定独立性显著提高，与对照ras转染的细胞相比，这也支持了上述观察结果。最后，R1过表达的人结肠癌细胞也显示出恶性潜能降低的特征。这些结果表明，核糖核苷酸还原酶的两个组成部分都是独特的恶性肿瘤决定因素，在其调控中发挥相反的作用，在恶性肿瘤的机制中存在一个新的重要控制点，这涉及R1和R2表达水平的平衡，而这种平衡的改变可以显著改变转化、致瘤性和转移潜力。
Our recent studies have shown that deregulated expression of R2, the rate-limiting component of ribonucleotide reductase, enhances transformation and malignant potential by cooperating with activated oncogenes, We now demonstrate that the R1 component of ribonucleotide reductase has tumor-suppressing activity, Stable expression of a biologically active ectopic R1 in ras transformed mouse fibroblast 10T1/2 cell lines, with or without R2 overexpression, led to significantly reduced colony-forming efficiency in soft agar, The decreased anchorage independence was accompanied by markedly suppressed malignant potential in vivo. In three ras-transformed cell lines, R1 overexpression resulted in abrogation or marked suppression of tumorigenicity, In addition, the ability to form lung metastases by cells overexpressing R1 was reduced by >85%. Metastasis suppressing activity also was observed in the highly malignant mouse 10T1/2 derived RMP-6 cell line, which was transformed by a combination of oncogenic I as, myc, and mutant p53. Furthermore, in support of the above observations with the R1 overexpressing cells, NIH 3T3 cells cotransfected with an R1 antisense sequence and oncogenic ras showed significantly increased anchorage independence as compared with control ras-transfected cells, Finally, characteristics of reduced malignant potential also were demonstrated with R1 overexpressing human colon carcinoma cells, Taken together, these results indicate that the two components of ribonucleotide reductase both are unique malignancy determinants playing opposing roles in its regulation, that there is a novel control point important in mechanisms of malignancy, which involves a balance in the levels of R1 and R2 expression, and that alterations in this balance can significantly modify transformation, tumorigenicity, and metastatic potential.