Mutations of N-Terminal Regions Render the Retinoblastoma Protein Insufficient for Functions in Development and Tumor Suppression

Abstract

To assess biological roles of the retinoblastoma protein (RB), four independent transgenic mouse lines expressing human RB with different deletions in the N-terminal region (RBΔN) were generated and compared with mice expressing identically regulated, full-length RB. Expression of both RB and RBΔN caused developmental growth retardation, but the wild-type protein was more potent. In contrast to wild-type RB, the RBΔN proteins were unable to rescue Rb^−/− mice completely from embryonic lethality. Embryos survived until gestational day 18.5 but displayed defects in the terminal differentiation of erythrocytes, neurons, and skeletal muscle. In Rb^+/− mice, expression of the RBΔN transgenes failed to prevent pituitary melanotroph tumors but delayed tumor formation or progression. These results strongly suggest that N-terminal regions are crucial for embryonic and postnatal development, tumor suppression, and the functional integrity of the entire RB protein. Furthermore, these transgenic mice provide models that may begin to explain human families with low-penetrance retinoblastoma and mutations in N-terminal regions of RB.