p27kip1: A Multifunctional Cyclin-Dependent Kinase Inhibitor with Prognostic Significance in Human Cancers

Abstract

p27kip1 (p27) is a member of the universal cyclin-dependent kinase inhibitor (CDKI) family. p27 expression is regulated by cell contact inhibition and by specific growth factors, such as transforming growth factor (TGF)-beta. Since the cloning of the p27 gene in 1994, a host of other functions have been associated with this cell cycle protein. In addition to its role as a CDKI, p27 is a putative tumor suppressor gene, regulator of drug resistance in solid tumors, and promoter of apoptosis; acts as a safeguard against inflammatory injury; and has a role in cell differentiation. The level of p27 protein expression decreases during tumor development and progression in some epithelial, lymphoid, and endocrine tissues. This decrease occurs mainly at the post-translational level with protein degradation by the ubiquitin-proteasome pathway. A large number of studies have characterized p27 as an independent prognostic factor in various human cancers, including breast, colon, and prostate adenocarcinomas. Here we review the role of p27 in the regulation of the cell cycle and other cell functions and as a diagnostic and prognostic marker in human neoplasms. We also review studies indicating the increasingly important roles of p27, other CDKIs, and cyclins in endocrine cell hyperplasia and tumor development.

Expression of p27Kip1 Protein in Transitional Cell Carcinoma of the Upper Urinary Tract

“…On this basis, the detection of p27 Kip1 protein would appear to be of little or no value in predicting tumor progression in TCC-UUT. p27 Kip1 protein blocks progression from the G1 to the S phase of the cell cycle and is highly expressed in cells arrested at the G0 or G1 phase (2)(3)(4). Recent reports have indicated that expression of p27 Kip1 protein is inversely related to proliferative activity (as measured using Ki-67 antibody) in cells at all stages except the G0 phase in non-small-cell lung carcinomas, endocrine tumors, and malignant lymphomas (25)(26)(27).…”

“…plexes, which play important regulatory roles during cell cycle progression (1)(2)(3), are negatively regulated by CDK inhibitors. These inhibitors are assigned to two families on the basis of their structural and functional properties.…”

“…The Cip/Kip family member p27 Kip1 regulates progression from G1 into S phase by binding and inhibiting the cyclin E/CDK2 complex necessary for entry into S phase (2)(3)(4). p27 Kip1 is present in large amounts in quiescent cells but has been found to be decreased in malignant tumors.…”

Proteasome inhibitor induced gene expression profiles reveal overexpression of transcriptional regulators ATF3, GADD153 and MAD1

“…The contribution of key cell cycle regulatory proteins, like p21 and p27, to proteasome inhibitor-induced cell cycle arrest has been well established Lloyd et al, 1999).…”

Increase in p21 expression independent of the p53 pathway in bleomycin-induced lung fibrosis

“…The increase in the degree of p27 staining could be either due to probable increase in TGF-h or due to changes in cell-cell interactions (Llyod et al, 1999;Slingerland and Pagano, 2000). It is quite difficult to make any conclusions about p27 since the effects of TGF-h, rapamycin, and contact inhibition on cell proliferation remained unchanged in p27 null mice (Nakayama et al, 1996).…”