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Novel Roles of RNase L in Prostate Cancer
Başlık:
Novel Roles of RNase L in Prostate Cancer
Yazar:
Dayal, Shubham, author.
ISBN:
9780438096530
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (137 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Committee members: Malathi Krishnamurthy; Douglas Leaman; Lirim Shemshedini; Roger Taylor; Eda Yildirim.
Özet:
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 SGCalpha1. 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 beta1 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.
Notlar:
School code: 0232
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(696343.1) | 696343-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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