Zhuang S M, Schippert A, Haugen-Strano A, Wiseman R W, Söderkvist P
Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Sweden.
Oncogene. 1998 Feb 12;16(6):803-8. doi: 10.1038/sj.onc.1201600.
The p16INK4a (alpha and beta form) and p15INK4b genes were analysed for homozygous deletion, hypermethylation and point mutation in B6C3F1 mouse lymphomas induced by 2',3'-dideoxycytidine or 1,3-butadiene. Although the p16INK4a-alpha gene appeared normal in DNA from 2',3'-dideoxycytidine-induced lymphomas, Southern analyses revealed homozygous deletions or rearrangements of the p16INK4a-beta and/or p15INK4b genes in four of 16 tumours. Surprisingly, two of these lymphomas showed exclusive deletions of the p16INK4a EIbeta exon. The p15INK4b promoter region was hypermethylated in two additional 2',3'-dideoxycytidine-induced lymphomas. In contrast, homozygous deletions spanning the p16INK4a and p15INK4b loci were observed in only two of 31 1,3-butadiene-induced tumours. Thus, these cyclin dependent kinase inhibitor genes may play a significant role in chemically induced mouse lymphomas and support the contention of tumour suppressor activity for the p19ARF protein encoded by the p16INK4a-beta gene. Different genetic pathways may be involved in the development of these chemically induced tumours since we have previously shown that mutations in p53 and ras genes are common in 1,3-butadiene- but not 2',3'-dideoxycytidine-induced lymphomas.
对由2',3'-二脱氧胞苷或1,3-丁二烯诱导的B6C3F1小鼠淋巴瘤中的p16INK4a（α和β形式）和p15INK4b基因进行了纯合缺失、高甲基化和点突变分析。虽然在2',3'-二脱氧胞苷诱导的淋巴瘤的DNA中p16INK4a-α基因看起来正常，但Southern分析显示，16个肿瘤中有4个存在p16INK4a-β和/或p15INK4b基因的纯合缺失或重排。令人惊讶的是，其中两个淋巴瘤显示p16INK4a EIβ外显子的排他性缺失。在另外两个2',3'-二脱氧胞苷诱导的淋巴瘤中，p15INK4b启动子区域发生了高甲基化。相比之下，在31个1,3-丁二烯诱导的肿瘤中，只有两个观察到跨越p16INK4a和p15INK4b基因座的纯合缺失。因此，这些细胞周期蛋白依赖性激酶抑制剂基因可能在化学诱导的小鼠淋巴瘤中发挥重要作用，并支持由p16INK4a-β基因编码的p19ARF蛋白具有肿瘤抑制活性的观点。由于我们之前已经表明，p53和ras基因的突变在1,3-丁二烯诱导的淋巴瘤中很常见，但在2',3'-二脱氧胞苷诱导的淋巴瘤中不常见，因此这些化学诱导的肿瘤的发生可能涉及不同的遗传途径。
