Tepper, Clifford G. - University of California, Davis - Department of Biochemistry and Molecular Medicine

研究领域

Androgen Independence Research: Dr. Tepper's laboratory is interested in identifying molecules that mediate survival of prostate cancer cells during androgen ablation therapy. We reasoned that adjuvant targeting of these molecules can delay or abolish the development of androgen independence by increasing apoptosis. To this end, we have utilized a combination of biochemical and microarray profiling to identify genes and pathways critical to androgen-independent survival. Data from the lab showed that the PI3K-Akt pathway is hyperactivated during androgen withdrawal (AW) and that pharmacological inhibition markedly induced apoptosis via combined FKHR transcription factor activation and diminished Bcl-2 expression. Regulation of Androgen Receptor Expression Androgen ablation therapy of prostate cancer diminishes the androgen receptor (AR) pathway by antagonizing its function, thereby leading to a marked reduction in AR protein expression. However, hormone-refractory disease is generally characterized by AR pathway reinstatement distinguished by elevated levels of AR. One goal of Dr. Tepper's lab is to better understand this phenomenon by focusing upon mechanisms regulating AR expression, degradation, and stability. Data from the lab has shown that counter-regulatory polypeptide growth factor and androgen signaling influence steady-state AR levels by promoting degradation and stability, respectively. In the absence of androgen, AR levels decline rapidly via Akt phosphorylation and ubiquitin-mediated degradation. This is deregulated in androgen-independent sublines as they exhibited elevated AR levels in the presence of Akt hyperactivation.

近期论文

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Gautschi, O., Tepper, C. G., Purnell, P. R., Izumiya, Y., Evans, C. P., Green, T. P., Desprez, P. Y., Lara, P. N., Gandara, D. R., Mack, P. C., Kung, H. J. Regulation of Id1 expression by SRC: implications for targeting of the bone morphogenetic protein pathway in cancer. Cancer Res, 2008 68(7): 2250-8. Burich, R. A., Holland, W. S., Vinall, R. L., Tepper, C., de Vere White, R. W., Mack, P. C. Genistein combined polysaccharide enhances activity of docetaxel, bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines. BJU Int, 2008 102: 1458-66. Shi, X. B., Tepper, C. G., de Vere White, R. W. Cancerous miRNAs and their regulation. Cell Cycle, 2008 7(11): 1529-38. Shi, X. B., Tepper, C. G., de Vere White, R. W. MicroRNAs and prostate cancer. J Cell Mol Med, 2008 12(5A): 1456-65. Guo, Z., Yang, X., Sun, F., Jiang, R., Linn, D. E., Chen, H., Kong, X., Melamed, J., Tepper, C. G., Kung, H. J., Brodie, A. M., Edwards, J., Qiu, Y. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res, 2009 69(6): 2305-13. Zou, J. X., Guo, L., Revenko, A. S., Tepper, C. G., Gemo, A. T., Kung, H. J., Chen, H. W. Androgen-induced coactivator ANCCA mediates specific androgen receptor signaling in prostate cancer. Cancer Res, 2009 69(8): 3339-46.