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Thesis-Shubham Dayal.pdf (3.08 MB)

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Novel Roles of RNase L in Prostate Cancer

Dayal, Shubham
http://orcid.org/0000-0003-0181-0729
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1492793747213566

Abstract Details

2017, Doctor of Philosophy, University of Toledo, 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 the nuclease activity of RNase L is dispensable for androgen signaling and cell migration. Our results show that mutations in RNase L found in HPC patients may promote prostate cancer by increasing expression of AR-response genes and cell motility and identify novel roles of RNase L as a prostate cancer susceptibility gene.
Malathi Krishnamurthy (Committee Chair)
Lirim Shemshedini (Committee Member)
Roger Taylor (Committee Member)
Douglas Leaman (Committee Member)
Eda Yildirim (Committee Member)
136 p.
Biology
Prostate Cancer; Cell Motility; Cell Migration; Androgen Receptor; RNase L; Hereditary Prostate Cancer 1; Filamin A; 2-5 A; Androgen; PSA; Integrin beta 1; FAK-Src; Rac-GTPase

Recommended Citations

Citations

  • Dayal, S. (2017). Novel Roles of RNase L in Prostate Cancer [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1492793747213566

    APA Style (7th edition)

  • Dayal, Shubham. Novel Roles of RNase L in Prostate Cancer. 2017. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1492793747213566.

    MLA Style (8th edition)

  • Dayal, Shubham. "Novel Roles of RNase L in Prostate Cancer." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1492793747213566

    Chicago Manual of Style (17th edition)

toledo1492793747213566
277
© 2017, all rights reserved.
This open access ETD is published by University of Toledo and OhioLINK.