Role of p27Kip1 and Cyclin-Dependent Kinase 2 in the Proliferation of Non-Small Cell Lung Cancer

Abstract

The cell cycle is governed by a family of cyclin-dependent kinases (Cdks). Cdk2 forms a functional complex with cyclin E and plays a pivotal role in the regulation of G1/S transition. Cdk2 activity is negatively regulated by interactions with inhibitors. p27 Kip1 , one of the most potent inhibitors of Cdk2, was recently identified as a powerful negative prognostic marker in non-small cell lung cancer as well as in colorectal and breast cancer. In the present study, the expression of p27 and Ki-67 antigen in nonneoplastic and cancerous lung tissues was determined by immunohistochemistry. After establishing that the antibody-measured p27 labeling index was a good reflection of the level of p27 expression measured by Western blotting , we show that p27 labeling index is decreased in cancerous lung tissues , compared with nonneoplastic lung tissues , and exhibits a significant inverse relation to the proliferation marker Ki-67 antigen , detected with monoclonal antibody MIB-1. Consistent with these data , all cancerous lung tissues showed enhanced degradation activity of p27 compared with nonneoplastic lung tissues and , in addition , increased levels of the phosphorylated form of Cdk2 , as determined with Western blot analysis. The H1 histone kinase activity associated with Cdk2 was also increased in non-small cell lung cancers. Statistical analysis showed that proliferative activity as measured by MIB-1 labeling index was highly correlated with Cdk2 activity (r ‫؍‬ 0.767 , P < 0.0015). These results suggest that p27 and Cdk2 may play an important role in the proliferation of non-small cell cancer. (Am J Pathol 1998, 153:505-513)

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

“…Alterations in p27 Kip1 warrant particular attention as p27 Kip1 protein levels are reduced in several types of cancer including melanoma (Catzavelos et al, 1997;Loda et al, 1997;Mori et al, 1997;Florenes et al, 1998;Kawana et al, 1998), and p27 Kip1 heterozygous mice are prone to induced tumor formation (Fero et al, 1998). B-RAF is mutated in approximately 70% of melanomas (Davies et al, 2002).…”

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

“…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). In the present study, no correlation was found between the expression of p27 Kip1 protein and the proliferative activity measured using PCNA antibody, which reacts with nuclei in the late G1 and S phases of the cell cycle.…”

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

“…Instead, the low levels of p27 protein that have been observed in many human cancers are due to enhanced proteolysis [47][48][49][50][51][52]. This suggested that proteins involved in p27 degradation may have oncogenic properties (see Fig.…”