Mendonca M S, Desmond L A, Temples T M, Farrington D L, Mayhugh B M
Radiation and Cancer Biology Laboratory, Department of Radiation Oncology, 975 West Walnut Street, IB-346, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Mutagenesis. 2000 May;15(3):187-93. doi: 10.1093/mutage/15.3.187.
Loss of active tumor suppressor alleles on fibroblast chromosomes 11 and 14 are involved in radiation-induced neoplastic transformation of human hybrid CGL1 cells. Loss of either chromosome 11 or 14 alone is not sufficient for neoplastic transformation. To gain insight into the potential functions of these tumor suppressor loci, we have investigated the effects of chromosome 11 or 14 loss on radiation-induced neoplastic transformation. We recently demonstrated that loss of chromosome 11 increases the susceptibility to X-ray induced cell killing, neoplastic transformation and the expression of delayed death. The data suggested that one possible function of the chromosome 11 tumor suppressor gene may be to help maintain genome stability after radiation damage. We postulated that if the chromosome 14 allele is functioning in a similar manner, then the loss of chromosome 14 may also make the hybrid cells more susceptible to radiation-induced cell killing and neoplastic transformation. A hybrid cell line which has lost one copy of chromosome 14 was isolated and designated CON3(-14). CON3(-14) cells were more sensitive to X-ray-induced cell killing when compared with parental CGL1 cells. However, the susceptibility to radiation-induced neoplastic transformation was significantly reduced (by a factor of two) compared with the parental CGL1 cells. The expression of delayed death in the progeny of the irradiated CON3(-14) cells, growing in transformation flasks, was similar to CGL1 cells during the 21 day assay period. Taken together, the data indicate that loss of chromosome 14 alone increased the X-ray sensitivity of the hybrid cells but reduced their susceptibility to radiation-induced neoplastic transformation. These data suggest that the tumor suppressor alleles on chromosomes 11 and 14 may be functionally distinct in terms of their regulation of genomic instability and neoplastic transformation after radiation exposure.
成纤维细胞11号和14号染色体上活性肿瘤抑制等位基因的缺失与辐射诱导的人杂交CGL1细胞的肿瘤转化有关。单独缺失11号或14号染色体不足以导致肿瘤转化。为了深入了解这些肿瘤抑制基因座的潜在功能，我们研究了11号或14号染色体缺失对辐射诱导肿瘤转化的影响。我们最近证明，11号染色体的缺失增加了对X射线诱导的细胞杀伤、肿瘤转化和延迟死亡表达的易感性。数据表明，11号染色体肿瘤抑制基因的一个可能功能可能是在辐射损伤后帮助维持基因组稳定性。我们推测，如果14号染色体等位基因以类似方式发挥作用，那么14号染色体的缺失也可能使杂交细胞更容易受到辐射诱导的细胞杀伤和肿瘤转化。分离出一个缺失了一条14号染色体拷贝的杂交细胞系，并将其命名为CON3(-14)。与亲代CGL1细胞相比，CON3(-14)细胞对X射线诱导的细胞杀伤更敏感。然而，与亲代CGL1细胞相比，其对辐射诱导肿瘤转化的易感性显著降低（降低了两倍）。在转化瓶中生长的经辐射的CON3(-14)细胞后代中延迟死亡的表达在21天的检测期内与CGL1细胞相似。综上所述，数据表明单独缺失14号染色体增加了杂交细胞对X射线的敏感性，但降低了它们对辐射诱导肿瘤转化的易感性。这些数据表明，11号和14号染色体上的肿瘤抑制等位基因在辐射暴露后对基因组不稳定性和肿瘤转化的调节方面可能在功能上有所不同。
