Diabetes results from an inadequate mass of functional beta cells, due to either beta cell loss caused by immune assault or the lack of compensation to overcome insulin resistance. Elucidating the mechanisms that regulate beta cell mass has important ramifications for fostering beta cell regeneration and the treatment of diabetes. We report here that Skp2, a substrate recognition component of S...

The universal cyclin-dependent kinase inhibitor p27(Kip1) functions as a tumor suppressor, and reduced levels of p27(Kip1) connote poor prognosis in several human malignancies. p27(Kip1) levels are predominately regulated by ubiquitin-mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCF(Skp2) complex following its phosphorylation by the cyclin E-cycli...

The abundance of the cyclin-dependent kinase (CDK) inhibitor p57Kip2, an important regulator of cell cycle progression, is thought to be controlled by the ubiquitin-proteasome pathway. The Skp1/Cul1/F-box (SCF)-type E3 ubiquitin ligase complex SCFSkp2 has now been shown to be responsible for regulating the cellular level of p57Kip2 by targeting it for ubiquitylation and proteolysis. The elimina...

We have previously reported that Nodal, a member of the TGF-beta superfamily, acts through activin receptor-like kinase 7 (ALK7) to inhibit ovarian cancer cell proliferation. To determine the mechanism underlying their effects, a cell cycle gene array was performed and cyclin G2 mRNA was found to be strongly up-regulated by Nodal and ALK7. To study the function and regulation of cyclin G2 in ov...

TSC1 (tuberous sclerosis complex 1) encoding hamartin and TSC2 encoding tuberin are tumor suppressor genes responsible for the autosomal dominantly inherited disease tuberous sclerosis. These genes have been demonstrated to negatively regulate cell cycle progression, the activity of cdk2, and the degradation of the cyclin-dependent kinase inhibitor p27. To date, the underlying molecular mechani...

S phase kinase-associated protein 2 (Skp2) has been shown to be required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb) deficient mice. Here we have demonstrated that flavokawain A (FKA), a novel chalcone from the kava plant, selectively inhibited the growth of pRb deficient cell lines and resulted in a proteasome-dependent and ubiquitination-mediated Skp2 deg...

Arsenic trioxide (ATO) has been found to exert anti-cancer activity in various human malignancies. However, the molecular mechanisms by which ATO inhibits tumorigenesis are not fully elucidated. In the current study, we explored the molecular basis of ATO-mediated tumor growth inhibition in pancreatic cancer cells. We used multiple approaches such as MTT assay, wound healing assay, Transwell in...

The ubiquitin-recognition protein Ufd1 facilitates clearance of misfolded proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Here we report that prolonged ER stress represses Ufd1 expression to trigger cell cycle delay, which contributes to ERAD. Remarkably, down-regulation of Ufd1 enhances ubiquitination and destabilization of Skp2 mediated by the anaphase-p...

Breast cancer is the most common type of cancer among American women, and remains the second leading cause of cancer-related death for female in the United States. It has been known that several signaling pathways and various factors play critical roles in the development and progression of breast cancer, such as estrogen receptor, Notch, PTEN, human epidermal growth factor receptor 2, PI3K/Akt...

OBJECTIVE The aim of this study was to analyze the immunohistochemical expression of Skp2 protein in 38 oral nevi and 11 primary oral melanomas. STUDY DESIGN Expression of this ubiquitin protein was evaluated by immunohistochemistry in 49 oral melanocytic lesions, including 38 intramucosal nevi and 11 primary oral melanomas. The labeling index (LI) was assessed considering the percentage of c...