Alterations in the expression of the cell cycle regulatory protein cyclin kinase subunit 1 in colorectal carcinoma

Abstract

BACKGROUND Low levels of p27Kip1 are associated with high aggressiveness and poor prognosis in various malignancies, including colorectal carcinoma. The authors showed that S phase kinase protein 2 (Skp2), the specific ubiquitin ligase subunit that targets p27Kip1 for degradation, was overexpressed and was inversely related to p27Kip1 levels in patients with colorectal carcinoma. The essential role of cyclin kinase subunit 1 (Cks1) in Skp2‐dependent p27 degradation was recently discovered, but its role in human malignancies is unknown. METHODS Quick‐frozen colorectal tumor samples from 30 patients were separated by electrophoresis on sodium dodecyl sulfate–polyacrylamide gels, transferred to nitrocellulose, and probed with highly specific monoclonal antibodies directed against Cks1, Skp2, and p27Kip1. The expression of Cks1 was also examined by immunohistochemistry using formalin‐fixed, paraffin‐embedded tissue sections from the same patients. RESULTS A strong correlation was found between Cks1 levels and Skp2 expression and loss of tumor differentiation. A significant inverse relation was also observed between levels of Cks1 and p27Kip1 and overall survival. CONCLUSIONS The results of the current study suggest that increased expression of Cks1 may have an important causative role in decreasing levels of p27 in patients with aggressive colorectal carcinoma. Cancer 2004. © 2004 American Cancer Society.

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

“…Enhanced levels of Skp2 have been associated with several types of human cancer (Gstaiger et al, 2001) and, during the course of our work, have been detected in melanoma tissue sections (Li et al, 2004;Woenckhaus et al, 2005). Also, Cks1 levels are enhanced in non-small cell lung and colorectal carcinoma (Inui et al, 2003;Shapira et al, 2004). Second, Skp2 levels are dependent on adhesion and growth factors in human melanocytes, similar to findings in fibroblasts (Carrano and Pagano, 2001), and inversely correlate with the levels of p27 Kip1 (Bhatt et al, 2005).…”

“…Structural analysis indicates that p27 Kip1 interacts with both Cks1 and Skp2 (Hao et al, 2005). Knockout of either Skp2 or Cks1 in mice leads to increased p27 Kip1 levels (Nakayama et al, 2000;Spruck et al, 2001) and, notably, expression of Skp2 and Cks1 is enhanced in several cancers (Gstaiger et al, 2001;Latres et al, 2001;Inui et al, 2003;Shapira et al, 2004).…”

Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer

“…8,38 These two proteins have previously been implicated in different types of cancers. 15,[39][40][41][42][43] We observed increased expression of these two proteins in the higher-grade tumors. Cks1 is a sensitive marker for diagnosis and prognosis although its specificity remains low.…”

The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma

“…The authors of the current study have recently investigated the expression of Cks1 in colorectal carcinoma and its relation to p27 Kip1 and Skp2 levels. 16 Cks1 protein levels strongly correlated with Skp2 protein levels and inversely with those of p27 Kip1 . Further, Cks1 expression was upregulated in poorly differentiated tumors and advanced disease stage.…”

“…The specificity of immunohistochemistry staining for Skp2, Cks1, and p27 Kip1 was previously verified by comparing the expression of the proteins on immunohistochemistry with protein levels determined by immunoblot analysis from the same tumor specimens. 13,16 Grading of nuclear protein staining was also based on previous experiments from our laboratory and were compared with immunoblot analysis for semiquantification as high or low. 13,16 In brief, nuclear protein expression of epithelial cells only was scored as high if 50% or more of the nuclei were stained or low if less than 50% were stained.…”