p27(Kip1)-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

p27(Kip1) (p27) controls cell cycle progression by binding to and inhibitin g the activity of cyclin dependent kinases, Disruption of the p27 gene in m ice (p27-/-) results in increased body growth with a disproportionate enlar gement of the spleen, thymus, testis, ovary and pituitary, The increase in pituitary size is due to selective hyperplasia of the intermediate lobe (IL ) while the anterior lobe (AL) is not overtly affected. p27 heterozygous mi ce (p27+/-), as well as p27-/- mice, are hypersensitive to radiation- and c hemical-induced tumors compared to wildtype (p27+/+) littermates. Therefore , unlike classical tumor suppressors, only a reduction in p27 levels is nec essary to predispose tissues to secondary tumor promoters. Consistent with these studies is the fact that the p27 gene sequence and mRNA levels appear normal in human pituitary adenomas while p27 protein levels are decreased, Therefore, a reduction in p27 levels could be sufficient to sensitize pitu itary cells to tumorigenic factors, To test this hypothesis, metallothionei n promoter-driven, human growth hormone-releasing hormone (MT-hGHRH) transg enic mice, that exhibit somatotrope hyperplasia before 9 months of age and subsequent adenoma formation with 30-40% penetrance, were crossbred with p2 7+/- mice for two successive generations to produce p27+/+, p27+/- and p27- /- mice that expressed the hGHRH At 10-12 weeks of age, p27-/- and p27+/+, hGHRH mice were larger than their p27+/+ littermates and displayed characte ristic hyperplasia of the IL and AL, respectively, Expression of the hGHRH transgene in both p27+/- and p27-/- mice selectively expanded the populatio n of somatotropes within the AL, where pituitaries of p27+/-, hGHRH and p27 -/-, hGHRH mice were two- and fivefold larger than p27+/+, hGHRH pituitarie s, respectively, There was also a synergistic effect of hGHRH transgene exp ression and p27-deficiency on liver, spleen and ovarian growth, At 6-8 mont hs of age, 83% of p27+/-, hGHRH mice displayed macroscopic AL (>100 mg), wh ile all pituitaries from p27+/+, hGHRH mice remained hyperplastic (<20 mg), In contrast to the dramatic effects of p27-deficiency on hGHRH-induced org an growth, elimination of p53, by crossbreeding MT-hGHRH mice to p53-defici ent mice, did not augment the hyperplastic/tumorigenic effects of hGHRH tra nsgene expression, Taken together these results demonstrate that reduction in p27 expression is sufficient to sensitize somatotropes to the proliferat ive actions of excess GHRH, resulting in the earlier appearance and increas ed penetrance of hGHRH-induced pituitary tumors.