Regulation of PCNA Function by Tyrosine Phosphorylation in Prostate Cancer
Final rept. 2 Sep 2008-1 Sep 2012
CINCINNATI UNIV OH
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The proliferating cell nuclear antigen PCNA has been widely used as a molecular marker for tumor progression and patient prognosis in a variety of human cancers. The PCNA protein has two forms a non-functional chromatin-unbound form, and a functional chromatin-associated form. The latter form is associated with cancer and tumor progression. Currently, there are no assays which can distinguish these two, distinct forms of the PCNA protein. As a result of an inability to discriminate between the functional and non-functional types, relating PCNA levels in tumor tissues with patient prognosis has been difficult. The Principal Investigator PI recently discovered that the functional, chromatin-bound form of PCNA is phosphorylated at tyrosine residue Y211, and that the nonfunctional form is not phosphorylated at this residue. This distinguishing characteristic could provide a means for reliably differentiating between the two protein forms and allowing healthcare providers to utilize PCNA levels to make a more accurate assessment of tumor progression and patient prognosis. Additionally, the PI found that specifically inhibiting Y211 phosphorylation resulted in the degradation of the functional form of PCNA and suppressed its DNA synthesis and repair functions. This promising result suggests that blocking Y211 phosphorylation of PCNA could provide a means for inhibiting tumor growth in cancers in the future. The key objectives of this research are 1 Determine if blocking phospho-Y211 PCNA can lead to the suppression of prostate cancer cell proliferation and enhancement of chemosensitivity in prostate cancer cells 2 Examine whether phospho-Y211 PCNA is a good prognosis marker and whether its level in tissues is associated with key pathological characteristics of prostate cancer.
- Medicine and Medical Research