Skp2 is an oncoprotein that mediates the degradation of several negative regulators of the cell cycle to promote cell proliferation. A recent report by Huang and colleagues reveals that Skp2 directs the ubiquitylation and subsequent degradation of FoxO1, a member of the FoxO family of transcription factors. Since FoxO proteins possess tumor suppressor functions, this new finding suggests a new ...

Purpose: Skp2 is a subunit of the SCF ubiquitin protein ligase, which plays a vital role in the control of tumorigenesis via its regulationofG1-S transition. Deregulationof Skp2 invarious types of cancers correlates with aggressive clinical behavior and poor prognosis. Recent studies suggest that cell cycle ^ dependent fluctuation of Skp2 is governed byAPC, another important E3 ligase, thereby ...

Cyclin-dependent kinase inhibitors (CKIs) and Notch receptor activation have been shown to influence adult stem cells and progenitors by altering stem cell self-renewal and proliferation. Yet, no interaction between these molecular pathways has been defined. Here we show that ligand-independent and ligand-dependent activation of Notch1 induces transcription of the S phase kinase-associated prot...

The chromosomal translocation t(11;22) yields the EWS-Fli1 fusion gene and is associated with oncogenesis of Ewing family tumors (EFT). In this study, using the RNA interference method, we show that EWS-Fli1-targeting small interfering RNAs (siRNA) depleted EWS-Fli1 protein and caused growth inhibition in EFT cells with the accumulation of p27 protein and the down-regulation of Skp2 protein in ...

Histone deacetylase inhibitors (HDACIs) represent an intriguing class of pharmacologically active compounds. Currently, some HDACIs are FDA approved for cancer therapy and many others are in clinical trials, showing important clinical activities at well tolerated doses. HDACIs also interfere with the aging process and are involved in the control of inflammation and oxidative stress. In vitro, H...

PURPOSE To examine the expression of the p27(KIP1)in the normal and epithelial-scraped cornea and whether degradation of p27(KIP1)by Skp2 is involved in the regulation of cell proliferation in response to wounding of the corneal epithelium. METHODS C57Bl6, p27(KIP1-/-), Skp2(-/-), and Skp2(-/-)/p27(KIP1-/-) double-knockout mice were examined. Normal and epithelial-scraped corneas were analyze...

The dysregulation of pathways regulating cellular function is a frequent hallmark of cancer and the development of specific pathway inhibitors that alter tumor growth and progression are the focus of multiple recent studies. E3 ubiquitin ligases are a large group of diverse protein enzymes that specifically target proteins for clearance, and their importance to normal cellular function is illus...

Cell cycle progression is negatively regulated by the pocket proteins pRb, p107, and p130. However, the mechanisms responsible for this inhibition are not fully understood. Here, we show that overexpression of p107 in fibroblasts inhibits Cdk2 activation and delays S phase entry. The inhibition of Cdk2 activity is correlated with the accumulation of p27, consequent to a decreased degradation of...

Mounting evidence suggests that dynamic interactions between a tumor and its microenvironment play a critical role in tumor development, cell-cycle progression, and response to therapy. In this study, we used mantle cell lymphoma (MCL) as a model to characterize the mechanisms by which stroma regulate cell-cycle progression. We demonstrated that adhesion of MCL and other non-Hodgkin lymphoma (N...

Nuclear hormone receptor family member PPARγ plays an important role in mammary gland tumorigenesis. Previous studies have shown PPARγ has cytoplasmic activities upon tetradecanoyl phorbol acetate (TPA) stimulation. However, the clinical pathological significance of cytoplasmic PPARγ is not completely understood in human breast cancer. Skp2 is oncogenic, and its frequent amplification and overe...