Tumor Suppression by a Severely Truncated Species of Retinoblastoma Protein

Rb(+/+):Rb(−/−) chimeric mice are healthy until early in adulthood when they develop lethal pituitary tumors composed solely of Rb(−/−) cells. In an effort to delineate the minimal structures of the retinoblastoma protein necessary for RB tumor suppression function, chimeric animals derived from stably transfected RB(−/−) embryonic stem (ES) cells were generated. One such ES cell transfectant expressed a human RB allele encoding a stable, truncated nuclear derivative lacking residues 1 to 378 (Δ1-378). Others encoded either wild-type human RB or an internally deleted derivative of the Δ1-378 mutant. All gave rise to viable chimeric animals with comparable degrees of chimerism. However, unlike control mice derived, in part, from naive Rb(−/−) ES cells or from ES cells transformed by the double RB mutant, Δ1-378/Δexon22, animals derived from either wild-type RB- or Δ1-378 RB-producing ES cells failed to develop pituitary tumors. Thus, in this setting, a substantial fraction of the RB sequence is unnecessary for RB-mediated tumor suppression.