Involvement of Novel Multifunctional Steroid Hormone Receptor Coactivator, E6-Associated Protein, in Prostate Gland Tumorigenesis PDF Download

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Languages : en
Pages : 20

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E3 ubiquitin-protein ligase enzyme, E6-associated protein (E6-AP), is a novel dual function steroid hormone receptor coactivator. E6-AP not only interacts with and enhances the hormonedependent transcriptional activities of various steroid hormone receptors, including androgen receptor (AR), but also is a member of the E3 class of functionally related ubiquitin-protein ligases. Previously, using E6-AP knockout animals we have shown that E6-AP is required for the proper development and growth of prostate gland. Furthermore, we also show that protein levels of the components of phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathway are decreased in E6-AP knockout animals. In this report we show that over expression of E6-AP in the prostate gland leads to increased prostate gland size and also showed PIN like precancerous lesions. We also found that PI3K-Akt pathway is elevated in E6-AP transgenic prostate gland. In addition to that, stable LNCaP cells that stably overexpress exogenous E6-AP protein have elevated levels of PI3K, total Akt, phosphorylated Akt (active Akt) suggesting that E6-AP regulates the PI3K-Akt signaling pathway. This report also suggest that E6-AP may regulate PI3K-Akt signaling by regulating the protein levels of RhoA, a small GTPase, which is a negative regulator of the Akt signaling pathway via the ubiquitinproteasome pathway. In addition, we show that stable overexpression of E6-AP in prostate cancer cells results in decreased apoptosis. Overall our data suggests that E6-AP regulates the PI3K-Akt pathway in prostate cells which results in increased prostate gland growth, proliferation and decreased apoptosis.