| RNase L is an endoribonuclease that functions in the molecular pathways of interferon (IFN) action against viral infections. Although the pro-apoptotic activity of RNase L is well known, how RNase L activation during viral infection leads to apoptosis is not clear. Recently, RNase L was considered to be a tumor suppressor based on its pro-apoptotic activity and mapping to hereditary prostate cancer allele 1 (HPC1). While involvement of a viral pathogen in prostate cancer was proposed (Silverman 2003), the unknown novel mechanism of RNase L in the suppression of prostate cancer progression still remains possible. Several lines of evidence implied that RNase L may possess an unidentified function: first, RNase L+/+ fibroblasts are different from RNase L-/- in morphology. Second, RNase L -/- mice showed a 5-day delayed rejection of skin allograft and a dramatic reduction in inflammatory infiltrates (Silverman RH et al 2002), indicating that RNase L play a role in immunosystem. Third, RNase L was found to interact with actin cytoskeleton (Tnani M et al 1998), and the interactions were abolished by PMA treatment of the cells. Finally, three inactivating mutations (M1I, E265X, and Delta157) and an additional nine missense variants (G59S, I97L, I220V, V247M, G296V, and S322F) in RNase L have been observed in prostate cancer cases. No mutation is mapped in the ribonuclease domain, indicating that ribonuclease domain might not be involved in RNtase L related pathogenesis in prostate cancer. My thesis thus focused the possible mechanisms of the antiviral and antitumor functions of RNase L.; In antiviral studies, my thesis showed that 2--5A, dsRNA and viral infection induced activation of the c-Jun NH2-terminal kinases (JNK) family of MAP kinases and viral induction of apoptosis are deficient in mouse cells lacking RNase L. In addition, 2--5A resulted in specific ribosomal RNA cleavage products coinciding with JNK activation. Moreover, 2--5A induced apoptosis was dramatically enhanced by IFN pretreatment in JNK1+/+ JNK2+/+ cells but not in Jnk1-/- Jnk2-/- cells. These findings suggest that JNK and RNase L function in an integrated signaling pathway during the IFN response that leads to elimination of virus-infected cells through apoptosis.; In antitumor studies, my research established that haptotaxis of RNase L-/- MEF cells increased about two fold, compared to their wildtype counterparts. (Abstract shortened by UMI.)... |
