Shore S K, Bogart S L, Reddy E P
Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104-4268.
Proc Natl Acad Sci U S A. 1990 Sep;87(17):6502-6. doi: 10.1073/pnas.87.17.6502.
Activation of the c-abl protooncogene occurs in Abelson murine leukemia virus, in Hardy-Zuckerman 2 feline sarcoma virus, and during the chromosomal translocations that generate BCR-ABL gene fusion products. To study the molecular mechanism involved in the c-abl activation, we have created a series of modifications in murine c-abl and assayed these constructs for oncogenic activity using the NIH 3T3 cell transformation assay. Our results show that amino-terminal deletions are sufficient for oncogenic activation of c-abl and high levels of oncogenic activities were generated by a deletion of 114 codons from the 5' end that deleted the SH3 region. A deletion of 53 codons from the 5' end (inclusive of deletions seen in Hardy-Zuckerman 2 feline sarcoma virus and BCR-ABL gene products) that retains the SH3 region of c-abl resulted in the generation of low levels of transforming activity. This transforming potential was substantially increased with the introduction of a G----A point mutation in codon 832 that is present in v-abl. The point mutation was found to affect the secondary structure and the tyrosine kinase activity of the mutant gene products.
c-abl原癌基因的激活发生在艾贝尔逊鼠白血病病毒、哈迪-祖克曼2型猫肉瘤病毒中，以及在产生BCR-ABL基因融合产物的染色体易位过程中。为了研究c-abl激活所涉及的分子机制，我们对鼠c-abl进行了一系列修饰，并使用NIH 3T3细胞转化试验检测这些构建体的致癌活性。我们的结果表明，氨基末端缺失足以使c-abl致癌激活，并且从5'端缺失114个密码子（该缺失删除了SH3区域）产生了高水平的致癌活性。从5'端缺失53个密码子（包括在哈迪-祖克曼2型猫肉瘤病毒和BCR-ABL基因产物中所见的缺失），保留了c-abl的SH3区域，导致产生低水平的转化活性。随着在v-abl中存在的第832位密码子引入G→A点突变，这种转化潜能大幅增加。发现该点突变影响突变基因产物的二级结构和酪氨酸激酶活性。
