WD-repeat proteins are very diverse, yet these are structurally related proteins that participate in a wide range of cellular functions. WDR13, a member of this family, is conserved from fishes to humans and localizes into the nucleus. To understand the in vivo function(s) of Wdr13 gene, we have created and characterized a mutant mouse strain lacking this gene. The mutant mice had higher serum insulin levels and increased pancreatic islet mass as a result of enhanced beta cell proliferation. While a known cell cycle inhibitor, p21, was downregulated in the mutant islets, over expression of WDR13 in the pancreatic beta cell line (MIN6) resulted in upregulation of p21, accompanied by retardation of cell proliferation. We suggest that WDR13 is a novel negative regulator of the pancreatic beta cell proliferation. Given the higher insulin levels and better glucose clearance in Wdr13 gene deficient mice, we propose that this protein may be a potential candidate drug target for ameliorating impaired glucose metabolism in diabetes.

Purpose:Overexpression of the inhibitors of apoptosis proteins have been demonstrated in a variety and of solid tumors including melanomas and nonmelanomas skin cancers. X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of apoptosis which prevents apoptosis by inhibiting caspases 9, 7, and 3. The prognostic value of XIAP in sebaceous gland carcinoma (SGC) remains unexplored.Methods:The immunohistochemical expression of XIAP was evaluated in 29 SGC cases.Results:The cytoplasmic overexpression of XIAP was detected in 62% SGC cases. XIAP expression was found to be significantly associated with advanced age, large tumor size, and with reduced disease-free survival (P = 0.0174). XIAP expression and advance tumor Grade III emerged as significant risk factors on univariate analysis. On stepwise multivariate analysis, both increased cytoplasmic XIAP expression and high tumor grade were found to be significantly associated with recurrence. Patients with low XIAP immunoexpression had a longer disease-specific survival than those with high expression in the 5-year follow-up.Conclusion:The present study demonstrates at the immunohistochemical level that XIAP is overexpressed in SGC and that high expression could be of biological significance in the development of eyelid SGC. Our finding suggests that up-regulation of XIAP may aggravate tumor metastasis in SGC.

endometrial hyperplasia (eH) is a condition where uterine endometrial glands show excessive proliferation of epithelial cells that may subsequently progress into endometrial cancer (ec). Modern lifestyle disorders such as obesity, hormonal changes and hyperinsulinemia are known risk factors for eH. A mouse strain that mimics most of these risk factors would be an ideal model to study the stagewise progression of eH disease and develop suitable treatment strategies. Wdr13, an X-linked gene, is evolutionarily conserved and expressed in several tissues including uteri. in the present study, Wdr13 knockout female mice developed benign proliferative epithelium that progressed into eH at around one year of age accompanied by an increase in body weight and elevated estradiol levels. Molecular characterization studies revealed increase in ERα, PI3K and a decrease in PAX2 and ERβ proteins in Wdr13 mutant mice uteri. Further, a decrease in the mRNA levels of cell cycle inhibitors, namely; p21 and cyclin G2 was seen. Leukocyte infiltration was observed in the uterine tissue of knockout mice at around 12 months of age. These physiological, molecular and pathological patterns were similar to those routinely seen in human EH disease and demonstrated the importance of WDR13 in mice uterine tissue. thus, the genetic loss of Wdr13 in these mice led to mimicking of the human eH associated metabolic disorders making Wdr13 knockout female mice a potential animal model to study human endometrial hyperplasia. Endometrial hyperplasia (EH) is a precancerous condition for endometrial carcinoma (EC) marked with abnormal proliferation of endometrial cells 1,2. EC is one of the most common reproductive cancers in females 3,4 accounting for 90% of uterine cancers 5. Although EH is a common gynecologic disease, information on the progression of EH to EC and its pathogenesis is scanty. It is now increasingly understood that modern lifestyle metabolic syndromes involving obesity, elevated estradiol, hyperinsulinemia are known risk factors for EH which generally advances to EC 4,6. Hence, it is critical to understand the underlying mechanisms and the pathophysiology of EH. Mouse models are important tools in identifying the mechanisms underlying the development of EH as well as to test the drugs for EH treatment 7. Some of the genetically modified mouse models available to study EH include Beta-catenin and Transforming growth factor-β knockout mice 2,5. Genetic mouse models implicate the importance of the specific gene in the development of EH disease. However, these mice do not replicate the human EH condition that developed due to metabolic disorders such as obesity, elevated estradiol, hyperinsulinemia etc. Thus, mice which may mimic the human risk factors for EH without forcible induction would be an appropriate model to study EH and to develop drugs for EH treatment. WDR13 protein belongs to WD-repeat containing family of proteins with diverse functions 8,9. Wdr13 gene is X-linked and conserved across vertebrates with 87% homology between h...

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