Doctor of Philosophy, University of Toledo, 2017, Biology (Cell-Molecular Biology)
Prostate cancer is the second leading cause of cancer-related death in men in the U.S. Hereditary Prostate Cancer (HPC) accounts for 43% of early onset cases and 9% of all cases of cancer. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to an antiviral gene, RNase L. RNase L is a latent endoribonuclease that is activated by a unique ligand, 2-5A, produced from cellular ATP in virally-infected cells. To date there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression. In these studies we demonstrate the role of RNase L, which does not require nuclease activity, in regulating transcription of androgen-responsive genes, cell migration and activity of matrix metalloproteinases, suggesting a novel role as a tumor suppressor. Here we show that both RNase L and Filamin A bind to AR, and the interaction is regulated by androgens. Further, RNase L regulates ligand-dependent AR translocation to the nucleus and transcription of androgen-response genes. Cells with reduced levels of RNase L or Filamin A show increased AR translocation to the nucleus and this is accompanied by an increase in expression of androgen-response genes, PSA, ETV1 and SGCa1. Expression of RNase L mutants R462Q and E265X, which are most prevalent in HPC patients, in cells lacking endogenous RNase L resulted in increased AR translocation accompanied by increased transcription of AR-responsive genes. In addition, RNase L negatively regulates cell migration and cell attachment on various extracellular matrices. Cells with reduced RNase L levels promote cell surface expression of integrin ß1 which in turn activates FAK-Src pathway and Rac-GTPase activity to increase cell migration. Activity of MMP-2 and -9 is significantly increased in cells where RNase L levels are ablated. Mutants of RNase L with defects in binding the ligand 2-5A, defective in dimerization or lacking nuclease activity suggest that (open full item for complete abstract)
Committee: Malathi Krishnamurthy (Committee Chair); Lirim Shemshedini (Committee Member); Roger Taylor (Committee Member); Douglas Leaman (Committee Member); Eda Yildirim (Committee Member)
Subjects: Biology