Department of Pathology, New York University Langone Medical Center, New York, NY 10016, USA.
Carcinogenesis. 2012 Mar;33(3):708-13. doi: 10.1093/carcin/bgs003. Epub 2012 Jan 6.
To investigate if the cooperation between the Rgr oncogene and the inactivation of INK4b (a CDK inhibitor), as described previously in a sarcoma model, would be operational in a lymphoid system in vivo, we generated a transgenic/knockout murine model. Transgenic mice expressing the Rgr oncogene under a CD4 promoter were crossed into a p15(INK4b)-deficient background. Unexpectedly, mice with a complete ablation of both p15(INK4b) alleles had a lower tumor incidence and higher survival rate when compared with CD4-Rgr progeny with homozygous or heterozygous expression of p15(INK4b). Also, a similar survival pattern was observed in a parallel model in which transgenic mice expressing a constitutively activated N-Ras mutant were crossed into a p15(INK4b)-deficient background. To analyze this paradoxical event, we investigated the hypothesis that the absence of both p15(INK4b) alleles in the presence of the Rgr oncogene could be deleterious for proper thymocyte development. When analyzed, thymocyte development was blocked at the double negative (DN) 3 and DN4 stages in mice missing one or both alleles of p15(INK4b), respectively. We found reduction in overall apoptotic levels in the thymocytes of mice expressing Rgr, compared with their wild-type mice, supporting thymocyte escape from programmed cell death and subsequently facilitating the onset of thymic lymphomas but less for those missing both p15 alleles. These findings provide evidence of the complex interplay between oncogenes and tumor suppressor genes in tumor development and indicate that in the lymphoid tissue the inactivation of both p15 alleles is unlikely to be the first event in tumor development.
为了研究 Rgr 癌基因与 INK4b（一种 CDK 抑制剂）失活之间的合作关系是否像先前在肉瘤模型中描述的那样在体内淋巴系统中起作用，我们生成了一种转基因/敲除鼠模型。表达 Rgr 癌基因的转基因小鼠在 CD4 启动子的控制下进行表达，并与 p15(INK4b)缺陷型背景进行杂交。出乎意料的是，与具有纯合或杂合 p15(INK4b)表达的 CD4-Rgr 后代相比，完全缺失两个 p15(INK4b)等位基因的小鼠的肿瘤发生率更低，存活率更高。同样，在另一个平行模型中，表达组成型激活 N-Ras 突变体的转基因小鼠与 p15(INK4b)缺陷型背景进行杂交，也观察到了类似的存活模式。为了分析这种矛盾的现象，我们提出了一个假设，即在存在 Rgr 癌基因的情况下，两个 p15(INK4b)等位基因的缺失可能对胸腺细胞的正常发育有害。当分析时，分别缺失一个或两个 p15(INK4b)等位基因的小鼠，胸腺细胞发育在双阴性 (DN) 3 和 DN4 阶段受阻。我们发现，与野生型小鼠相比，表达 Rgr 的小鼠的胸腺细胞整体凋亡水平降低，支持胸腺细胞逃避程序性细胞死亡，从而促进了胸腺淋巴瘤的发生，但缺失两个 p15 等位基因的小鼠则不然。这些发现为肿瘤发生过程中癌基因和肿瘤抑制基因之间的复杂相互作用提供了证据，并表明在淋巴组织中，两个 p15 等位基因的失活不太可能是肿瘤发生的第一个事件。
