Quantitative effects of the retinoblastoma gene on mouse development and tissue-specific tumorigenesis

Models for studying the quantitative effects of RB protein in development and in tumorigenesis have been constructed. By crossing transgenic mice carrying the human Rb gene with mice heterozygous for the normal mouse Rb gene, we have generated mice that contain varying copies of the human Rb transgene and express varying amounts of human RB protein. Herein, we show that different amounts of RB protein are required to rescue two different phenotypes resulting from Rb deficiency: death during fetal development and susceptibility to cancer. Normal fetal development seems to depend on expression of critical amounts of RB protein, > or = 50% of the amount in wild-type mice. Adult mice, even if they overexpress RB protein, are prone to cancer if their cells express from only one Rb gene allele. Mice expressing small amounts of RB protein from different Rb alleles, however, are protected from cancer. Tumor suppression in cancer-prone cells, therefore, rather than depending on an absolute amount of RB protein, more directly depends on having redundancy in the Rb gene, assuring that at least one copy of a gene encoding functional RB protein is always available.