Fromm L, Shawlot W, Gunning K, Butel J S, Overbeek P A
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030.
Mol Cell Biol. 1994 Oct;14(10):6743-54. doi: 10.1128/mcb.14.10.6743-6754.1994.
Regulation of the cell cycle is a critical aspect of cellular proliferation, differentiation, and transformation. In many cell types, the differentiation process is accompanied by a loss of proliferative capability, so that terminally differentiated cells become postmitotic and no longer progress through the cell cycle. In the experiments described here, the ocular lens has been used as a system to examine the role of the retinoblastoma protein (pRb) family in regulation of the cell cycle during differentiation. The ocular lens is an ideal system for such studies, since it is composed of just two cell types: epithelial cells, which are capable of proliferation, and fiber cells, which are postmitotic. In order to inactivate pRb in viable mice, genes encoding either a truncated version of simian virus 40 large T antigen or the E7 protein of human papillomavirus were expressed in a lens-specific fashion in transgenic mice. Lens fiber cells in the transgenic mice were found to incorporate bromodeoxyuridine, implying inappropriate entry into the cell cycle. Surprisingly, the lens fiber cells did not proliferate as tumor cells but instead underwent programmed cell death, resulting in lens ablation and microphthalmia. Analogous lens alterations did not occur in mice expressing a modified version of the truncated T antigen that was mutated in the binding domain for the pRb family. These experimental results indicate that the retinoblastoma protein family plays a crucial role in blocking cell cycle progression and maintaining terminal differentiation in lens fiber cells. Apoptotic cell death ensues when fiber cells are induced to remain in or reenter the cell cycle.
细胞周期的调控是细胞增殖、分化和转化的一个关键方面。在许多细胞类型中，分化过程伴随着增殖能力的丧失，因此终末分化细胞进入有丝分裂后期，不再经历细胞周期。在本文所述的实验中，晶状体被用作一个系统来研究视网膜母细胞瘤蛋白（pRb）家族在分化过程中对细胞周期调控的作用。晶状体是进行此类研究的理想系统，因为它仅由两种细胞类型组成：能够增殖的上皮细胞和处于有丝分裂后期的纤维细胞。为了在存活小鼠中使pRb失活，编码猿猴病毒40大T抗原截短版本或人乳头瘤病毒E7蛋白的基因在转基因小鼠中以晶状体特异性方式表达。在转基因小鼠的晶状体纤维细胞中发现掺入了溴脱氧尿苷，这意味着不恰当地进入了细胞周期。令人惊讶的是，晶状体纤维细胞并没有像肿瘤细胞那样增殖，而是经历了程序性细胞死亡，导致晶状体消融和小眼症。在表达截短T抗原修饰版本（该版本在与pRb家族结合域发生突变）的小鼠中未出现类似的晶状体改变。这些实验结果表明，视网膜母细胞瘤蛋白家族在阻断晶状体纤维细胞的细胞周期进程和维持终末分化中起关键作用。当纤维细胞被诱导停留在或重新进入细胞周期时，会发生凋亡性细胞死亡。
