Skp2 is oncogenic and overexpressed in human cancers

Abstract

Skp2 is a member of the F-box family of substrate-recognition subunits of SCF ubiquitin-protein ligase complexes that has been implicated in the ubiquitin-mediated degradation of several key regulators of mammalian G1 progression, including the cyclindependent kinase inhibitor p27, a dosage-dependent tumor suppressor protein. In this study, we examined Skp2 and p27 protein expression by immunohistochemistry in normal oral epithelium and in different stages of malignant oral cancer progression, including dysplasia and oral squamous cell carcinoma. We found that increased levels of Skp2 protein are associated with reduced p27 in a subset of oral epithelial dysplasias and carcinomas compared with normal epithelial controls. Tumors with high Skp2 (>20% positive cells) expression invariably showed reduced or absent p27 and tumors with high p27 (>20% positive cells) expression rarely showed Skp2 positivity. Increased Skp2 protein levels were not always correlated with increased cell proliferation (assayed by Ki-67 staining), suggesting that alterations of Skp2 may contribute to the malignant phenotype without affecting proliferation. Skp2 protein overexpression may lead to accelerated p27 proteolysis and contribute to malignant progression from dysplasia to oral epithelial carcinoma. Moreover, we also demonstrate that Skp2 has oncogenic potential by showing that Skp2 cooperates with H-Ras G12V to malignantly transform primary rodent fibroblasts as scored by colony formation in soft agar and tumor formation in nude mice. The observations that Skp2 can mediate transformation and is up-regulated during oral epithelial carcinogenesis support a role for Skp2 as a protooncogene in human tumors.

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

“…First, we show that both Skp2 and Cks1 expression is enhanced in human melanoma cells lines compared to melanocytes. 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).…”

“…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).…”

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

“…3). In particular, Skp2 levels have been examined in human tumors and have been shown to correlate with grade of malignancy [51,[53][54][55][56][57]69,70]. Similar findings have been reported for high levels of cyclin E and A (reviewed in [58]).…”

“…Immunohistochemical studies revealed that high levels of Skp2 and low levels of p27 correlate with high grade malignancy in lymphomas [53]. Moreover, investigations of oral tissues have shown that Skp2 levels are elevated in epithelial adenomas and continue to increase during progression to carcinomas [54], while expression of Skp2 correlates with poor prognosis of oral cancer [51]. Recent studies have shown that Skp2 is overexpressed in breast carcinomas that are negative for both the estrogen receptor (ER) and Erb2-neu [57].…”

Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1–S transition

“…Overexpression or Regulation of RASSF1A by Skp2 at G 1 -S transition MS Song et al amplification of Skp2 has been reported in a large number of human cancers (Yokoi et al, 2002) and transgenic expression of Skp2 in mice leads to tumor formation, suggesting that Skp2 is oncogenic (Gstaiger et al, 2001;Latres et al, 2001). Skp2 targets p27, cyclin E and FOXO1 for degradation in a phosphorylationdependent manner (Marti et al, 1999;Nakayama et al, 2000;Huang et al, 2005).…”