THE RETINOBLASTOMA PROTEIN-BINDING REGION OF SIMIAN-VIRUS-40 LARGE T-ANTIGEN ALTERS CELL-CYCLE REGULATION IN LENSES OF TRANSGENIC MICE

Regulation of the cell cycle is a critical aspect of cellular prolifer ation, differentiation, and transformation. In many cell types, the di fferentiation process is accompanied by a loss of prolferative capabil ity, 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 cyc le during differentiation. The ocular lens is an ideal system for such studies, since it is composed of just two cell types: epithelial cell s, which are capable of proliferation, and fiber cells, which are post mitotic. In order to inactivate pRb in viable mice, genes encoding eit her a truncated version of simian virus 40 large T antigen or the E7 p rotein of human papillomavirus were expressed in a lens-specific fashi on in transgenic mice. Lens fiber cells in the transgenic mice were fo und to incorporate bromodeoxyuridine, implying inappropriate entry int o the cell cycle. Surprisingly, the lens fiber cells did not prolifera te as tumor cells but instead underwent programmed cell death, resulti ng in lens ablation and microphthalmia. Analogous lens alterations did not occur in mice expressing a modified version of the truncated T an tigen 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 maintainin g terminal differentiation in lens fiber cells. Apoptotic cell death e nsues when fiber cells are induced to remain in or reenter the cell cy cle.