Telomerase activity is selectively activated in the majority of human tumors, including prostate cancer and is critical for human cells to escape from crisis. Telomerase is believed to be important for oncogenesis and may provide a promising new target for selectively inhibiting growth of malignant cells. Although the telomerase catalytic subunit hTERT is transcriptionally activated by some oncogenes, little is known about the regulation of telomerase activity. Furthermore, the significance of telomerase activity for the development of cancer is not fully understood. By searching for proteins interacting with Pin2/TRF1, a telomere protein known to regulate telomere length, I identified the potent telomerase inhibitor PinX1. PinX1 and its small telomerase inhibitory domain (TID) directly interact with hTERT and potently inhibit its activity in vitro. Furthermore, overexpression of PinX1 or its TID potently inhibits telomerase activity and induces tumor cells into crisis. In contrast, depletion of endogenous PinX1 increases telomerase activity and elongates telomeres. These results demonstrate PinX1 to be the fist endogenous telomerase inhibitor to be identified. More importantly, depletion of PinXI also increases tumorigenicity in nude mice. Furthermore, the human PinX1 gene is located at chromosome 8p23, a region with frequent loss of heterozygosity (LOH) in a number of human cancers, especially in prostate cancer. Moreover, my preliminary analysis reveals that PinX1 expression is significantly reduced or is not detectable in many prostate cancer samples. These results suggest that PinX1 is a strong candidate for the long sought prostate cancer tumor suppressor located at 8p23. In this proposal, I will first determine PinX1 expression in prostate cancer tissues. Next, I will screen for possible genetic alterations in the PinX1 gene in prostate cancer. Finally, I will use Cre- and loxP-mediated recombination to generate conventional or prostate-specific PinX1-deficient mice to determine the role of PinX1 in the development of prostate cancer. These studies may provide novel insights into understanding the oncogenesis of prostate cancer, and might have novel implications for the development of new diagnostic and therapeutic procedures. Furthermore, these pilot studies are novel and will serve as the first step in obtaining R01 support from NIH to start a new project on prostate cancer.
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