51343

FZR1

CDC20C|CDH1|FZR|FZR2|HCDH|HCDH1;fizzy/cell division cycle 20 related 1 (Drosophila);FZR1;fizzy/cell division cycle 20 related 1 (Drosophila)

CDC20-like 1b|CDC20-like protein 1|cdh1/Hct1 homolog|fizzy-related protein homolog

19p13.3

protein-coding

As a subunit of a ubiquitin ligase, Skp2 is implicated in facilitating cell cycle progression via degradation of various protein targets. We report here that Skp2 is rapidly degraded following cellular stimulation by the cytokine transforming growth factor beta (TGF-beta) and that this degradation stabilizes the cell cycle arrest protein p27. The Skp2 degradation is mediated by Cdh1-anaphase-promoting complex (APC), as shown by depletion of Cdh1 with small interfering RNA, and by reconstitution of ubiquitylation reactions in a purified system. Blockage of Skp2 degradation greatly reduces TGF-beta-induced cell cycle arrest, as does expression of a nondegradable Skp2 mutant. Furthermore, we demonstrate that TGF-beta-induced Skp2 degradation is mediated by the Smad cascade. The degradation of Skp2 stabilizes p27, thereby ensuring TGF-beta-induced cell cycle arrest. These results identify a novel mechanism for tumor suppression by TGF-beta and explain why dysfunction of APC in the TGF-beta pathway in responsive cells is associated with cancer.

PURPOSE: Skp2 is a subunit of the SCF ubiquitin protein ligase, which plays a vital role in the control of tumorigenesis via its regulation of G(1)-S transition. Deregulation of Skp2 in various types of cancers correlates with aggressive clinical behavior and poor prognosis. Recent studies suggest that cell cycle-dependent fluctuation of Skp2 is governed by APC(Cdh1), another important E3 ligase, thereby preventing premature entry into S phase. To assess the potential role of APC(Cdh1) in tumorigenesis through proteolysis of Skp2, we have dissected the APC(Cdh1)-Skp2 cascade. EXPERIMENTAL DESIGN: We manipulated the APC(Cdh1)-Skp2 cascade and examined its cellular behavior using both breast cancer and normal breast epithelial cells. Furthermore, applying immunohistochemistry, we analyzed the clinicopathologic significance of these molecules in patients with breast cancer. RESULTS: Analysis of tissue arrays indicated that the percentage of samples positive for Cdh1 in breast cancer was significantly lower compared with normal breast tissues (P=0.004). Conversely, the percentage of samples scored as positive for Skp2 in cancer was significantly higher than in normal tissues (P<0.001). Moreover, prognostic studies revealed that relatively high levels of Cdh1 are associated with survivability in patients with breast cancer. In addition, depletion of Cdh1 by small interfering RNA in normal breast cells resulted in increased cellular proliferation, whereas knockdown of Skp2 significantly suppressed growth in breast cancer cells. CONCLUSIONS: This study shows a correlation between Skp2 and APC(Cdh1) in breast cancer. Thus, Cdh1 may act as an important component in tumor suppression and could be considered as a novel biomarker in breast cancer.