p27 and Rb are on overlapping pathways suppressing tumorigenesis in mice

The commitment of cells to replicate and divide correlates with the activat ion of cyclin-dependent kinases and the inactivation of Rb, the product of the retinoblastoma tumor suppressor gene, Rb is a target of the cyclin-depe ndent kinases and, when phosphorylated, is inactivated. Biochemical studies exploring the nature of the relationship between cyclin-dependent kinase i nhibitors and Rb have supported the hypothesis that these proteins are on a linear pathway regulating commitment. We have been able to study this rela tionship by genetic means by examining the phenotype of Rb+/-p27-/- mice. T umors arise from the intermediate lobe cells of the pituitary gland in p27- /- mice, as well as in Rb +/- mice after loss of the remaining wild-type al lele of Rb. Using these mouse models, me examined the genetic interaction b etween Rb and p27, We found that the development of pituitary tumors in Rb/- mice correlated with a reduction in p27 mRNA and protein expression. To determine whether the loss of p27 was an indirect consequence of tumor form ation or a contributing factor to the development of this tumor, we analyze d the phenotype of Rb+/-p27-/- mice. We found that these mice developed pit uitary adenocarcinoma with loss of the remaining wild-type allele of Rb and a high-grade thyroid C cell carcinoma that was more aggressive than the di sease in either Rb +/- or p27-/- mice. Importantly, we detected both pituit ary and thyroid tumors earlier in the Rb +/-p27-/- mice. We therefore propo se that Rb and p27 cooperate to suppress tumor development by integrating d ifferent regulatory signals.