Mice Lacking p27 Display Increased Body Size, Multiple Organ Hyperplasia, Retinal Dysplasia, and Pituitary Tumors

Abstract

Mice lacking p27(Kip1) have been created by gene targeting in embryonic stem cells. These mice are larger than the control animals, with thymus, pituitary, and adrenal glands and gonadal organs exhibiting striking enlargement. CDK2 activity is elevated about 10-fold in p27(-/-) thymocytes. Development of ovarian follicles seems to be impaired, resulting in female sterility. Similar to mice with the Rb mutation, the p27(-/-) mice often develop pituitary tumors spontaneously. The retinas of the mutant mice show a disturbed organization of the normal cellular layer pattern. These findings indicate that p27(Kip1) acts to regulate the growth of a variety of cells. Unexpectedly, the cell cycle arrest mediated by TGFbeta, rapamycin, or contact inhibition remained intact in p27(-/-) cells, suggesting that p27(Kip1) is not required in these pathways.

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.…”

Antitumour effect of cyclin-dependent kinase inhibitors (p16INK4A, p18INK4C, p19INK4D, p21WAF1/CIP1 and p27KIP1) on malignant glioma cells

“…In contrast, p27 KIP1 declines in the presence of mitogenic growth factor signalling or interleukin-2 (Nourse et al, 1994;Cheng et al, 1998). p27 KIP1 -deficient mice develop a variety of abnormalities including multiorgan hyperplasia and pituitary tumours (Nakayama et al, 1996). Furthermore, the higher the levels of p27 KIP1 expression, the better the prognosis with regard to human malignant gliomas (Alleyne et al, 1999), breast cancer (Porter et al, 1997) or lung cancer (Esposito et al, 1997).…”

Abnormalities of apoptotic and cell cycle regulatory proteins in distinct histopathologic components of benign prostatic hyperplasia

“…Evidence for the role of p27 in prostate disease includes the observation that knockout mice with a p27À/À genotype demonstrate histologic benign prostatic hyperplasia. 16 Kyprianou's group has shown loss of p27 in prostatic carcinoma as well as the important observation that this loss is associated with higher proliferative activity and higher tumor grade. 17 Cordon-Cardo et al 18 have demonstrated loss of p27 in prostatic carcinoma, as well as diffuse p27 staining in normal prostate epithelium and a distinct absence of staining in BPH nodules.…”