A Syndrome of Multiorgan Hyperplasia with Features of Gigantism, Tumorigenesis, and Female Sterility in p27 -Deficient Mice

Abstract

Targeted disruption of the murine p27(Kip1) gene caused a gene dose-dependent increase in animal size without other gross morphologic abnormalities. All tissues were enlarged and contained more cells, although endocrine abnormalities were not evident. Thymic hyperplasia was associated with increased T lymphocyte proliferation, and T cells showed enhanced IL-2 responsiveness in vitro. Thus, p27 deficiency may cause a cell-autonomous defect resulting in enhanced proliferation in response to mitogens. In the spleen, the absence of p27 selectively enhanced proliferation of hematopoietic progenitor cells. p27 deletion, like deletion of the Rb gene, uniquely caused neoplastic growth of the pituitary pars intermedia, suggesting that p27 and Rb function in the same regulatory pathway. The absence of p27 also caused an ovulatory defect and female sterility. Maturation of secondary ovarian follicles into corpora lutea, which express high levels of p27, was markedly impaired.

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

“…In the absence of p27 (p277/7) growth rates were also accelerated and body weights achieved values similar to p27+/+, hGHRH mice. These observations are consistent with those reported for the original MThGHRH (Hammer et al, 1985;Mayo et al, 1988) and p277/7 (Nakayama et al, 1996;Kiyokawa et al, 1996;Fero et al, 1996) mouse strains, indicating that alterations in the genetic background did not signi®cantly alter the e ect of hGHRH transgene expression or p27-de®ciency on body growth. Reduction or elimination of p27 (+/7 or 7/7) accelerated the growth promoting e ects of the MT-hGHRH transgene in both male and female mice, with the most dramatic e ects observed in p277/7, hGHRH mice ( Figure 1).…”

“…The p277/7 mice in this study displayed generalized organomegaly with disproportionate enlargement of the spleen, pituitary, testis and ovaries (Table 1A,B and Figure 2), as previously reported (Nakayama et al, 1996;Kiyokawa et al, 1996;Fero et al, 1996). In p27+/+, hGHRH mice, as in the original MT-hGHRH mouse strain (Hammer et al, 1985;Mayo et al, 1988), the pituitary, liver, spleen, heart and kidneys were increased in size, compared to their wildtype (p27+/+) littermates (Table 1A,B), with disproportionate enlargement of the pituitary and liver (Figure 2).…”

“…Mice with homozygous disruption of the p27 gene (p277/7) are 15 ± 30% larger than their heterozygous (p27+/7) and wildtype (p27+/+) littermates (Nakayama et al, 1996;Kiyokawa et al, 1996;Fero et al, 1996). The increase in body weight is due to generalized organomegaly in addition to disproportionate enlargement of the spleen, thymus, testis, ovary and pituitary.…”

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

“…The importance of p27 Kip1 in the regulation of T-cell proliferation Nourse et al, 1994) has also been con®rmed by studies on p27 Kip1 -null mice (Fero et al, 1996;Kiyokawa et al, 1996;Nakayama et al, 1996). These animals were presented with increased proliferation of thymocytes, resulting in thymic hyperplasia and an increased responsiveness of splenic and thymic T-cells to IL-2, which, in turn, correlated with higher cyclin E-associated kinase activity.…”

Comparison of the effectiveness of adenovirus vectors expressing cyclin kinase inhibitors p16INK4A, p18INK4C, p19INK4D, p21WAF1/CIP1 and p27KIP1 in inducing cell cycle arrest, apoptosis and inhibition of tumorigenicity

“…Another CKI in the p21 family is p27, which mediates growth arrest induced by transforming growth factor b, contact inhibition, or serum deprivation, and is thought to play a critical role in negative regulation of cell division in vivo (Sherr, 1996). The phenotype of mice null for the p27 gene includes increased body size, female sterility and a high incidence of spontaneous pituitary tumours (Fero et al, 1996;Kiyokawa et al, 1996;Nakayama et al, 1996). Recently, high level expression of p27 from adenovirus (Ad) vectors has been shown to induce apoptosis in tumour cell lines Wang et al, 1997).…”