The antitumor efficacy of type I interferon (IFN-/) therapy is variable since it can induce either tumor cell growth inhibition or apoptosis. The underlying molecular mechanisms of type I IFN-induced apoptosis remain largely unknown. Defining the signaling pathways activated by type I IFNs leading to tumor cell destruction are of clinical importance. Our preliminary data indicates that a deficiency in STAT2 prevents cells from undergoing IFN- -induced apoptosis and this defect correlates with impaired expression of interferon stimulated genes (ISGs). We have found that the pro-apoptotic protein Bim, which disrupts mitochondrial integrity, is activated by type I IFNs in a STAT2-dependent manner. Importantly, crosstalk between Bim and STAT2 signals likely exists since the apoptotic activity of type I IFNs is impaired in mouse embryonic fibroblasts deficient in either Bim or STAT2. Based on our data, our hypothesis is that type I IFN-induced STAT2 activity regulates the activation of the mitochondrial dependent death pathway by modulating the pro-apoptotic activities of BH3 domain only Bcl-2 proteins.
Specific Aims : 1) Determine the mechanism by which STAT2 modulates Bim activation. 2) Characterize conserved residues in STAT2 and determine whether they modulate type I IFN signaling and Bim activation. 3) Determine how STAT2 is required for the in vivo antitumor effects of type I IFNs. Significance: These results will provide insights into the signaling mechanisms and antitumor efficacy of type I IFN-induced apoptosis that are regulated by STAT2 and Bim.
Statement Interferons are a family of soluble proteins that are known for their function in antiviral host defense and cell growth inhibition. STAT2 is a critical molecule required for mediating the antiviral effects of IFN but little is known about its functional role in cancer. Our project will address a molecular mechanism by which interferons restrict tumor growth.
| Steen, Håkan C; Kotredes, Kevin P; Nogusa, Shoko et al. (2016) Phosphorylation of STAT2 on serine-734 negatively regulates the IFN-?-induced antiviral response. J Cell Sci 129:4190-4199 |
| Yue, Chanyu; Xu, Jun; Tan Estioko, Marc Daryl et al. (2015) Host STAT2/type I interferon axis controls tumor growth. Int J Cancer 136:117-26 |
| Sheikh, Faruk; Dickensheets, Harold; Gamero, Ana M et al. (2014) An essential role for IFN-? in the induction of IFN-stimulated gene expression by LPS in macrophages. J Leukoc Biol 96:591-600 |
| Steen, Håkan C; Nogusa, Shoko; Thapa, Roshan J et al. (2013) Identification of STAT2 serine 287 as a novel regulatory phosphorylation site in type I interferon-induced cellular responses. J Biol Chem 288:747-58 |
| Kotredes, Kevin P; Gamero, Ana M (2013) Interferons as inducers of apoptosis in malignant cells. J Interferon Cytokine Res 33:162-70 |
| Yue, Chanyu; Soboloff, Jonathan; Gamero, Ana M (2012) Control of type I interferon-induced cell death by Orai1-mediated calcium entry in T cells. J Biol Chem 287:3207-16 |
| Steen, Hakan C; Gamero, Ana M (2012) The role of signal transducer and activator of transcription-2 in the interferon response. J Interferon Cytokine Res 32:103-10 |
| Romero-Weaver, Ana L; Wang, Hsiang-Wen; Steen, Håkan C et al. (2010) Resistance to IFN-alpha-induced apoptosis is linked to a loss of STAT2. Mol Cancer Res 8:80-92 |
| Gamero, Ana M; Young, Matthew R; Mentor-Marcel, Roycelynn et al. (2010) STAT2 contributes to promotion of colorectal and skin carcinogenesis. Cancer Prev Res (Phila) 3:495-504 |
