The long range goal of the proposal is to investigate the mechanism of cap-independent translation of the c-myc protein with the assumption that its cellular function is a key determinant of tumor cell responses, especially for the malignancy multiple myeloma. More specifically, the proposal will elucidate how hnRNP A1 (A1) functions as a trans-acting protein that binds to the internal ribosome entry site (IRES) in the 5'UTR of the c-myc transcript, thus facilitating IRES-dependent translation of myc. Furthermore, it will focus on the ability of Akt and MAPK cascades to regulate this A1 translation-promoting activity, testing effects on the IRES-annealing activity of A1, effects on IRES-ribosome binding and effects on A1/IRES subcellular localization. Multiple myeloma cell lines, primary tumor cells and xenograft models will be used to exploit the insight gained on A1/myc IRES regulatory controls to understand mechanisms of myeloma progression due to IL-6 stimulation and myeloma therapy-resistance when treatment with mTOR inhibitors is attempted.
The project details the mechanism by which multiple myeloma cancer cells expand their numbers when they are stimulated by a growth factor called interleukin-6 (IL-6). This is an important pathway of progression of this malignancy in patients. It also elucidates how multiple myeloma tumor cells become resistant to promising new therapeutic agents called mTOR inhibitors.
|Shi, Yijiang; Daniels-Wells, Tracy R; Frost, Patrick et al. (2016) Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells. Cancer Res 76:5822-5831|
|Shi, Y; Yang, Y; Hoang, B et al. (2016) Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress. Oncogene 35:1015-24|
|Yoo, Esther M; Trinh, Kham R; Tran, Danh et al. (2015) Anti-CD138-targeted interferon is a potent therapeutic against multiple myeloma. J Interferon Cytokine Res 35:281-91|
|Shi, Yijiang; Frost, Patrick; Hoang, Bao et al. (2014) MNK1-induced eIF-4E phosphorylation in myeloma cells: a pathway mediating IL-6-induced expansion and expression of genes involved in metabolic and proteotoxic responses. PLoS One 9:e94011|
|Shi, Y; Frost, P; Hoang, B et al. (2013) MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells. Oncogene 32:190-7|
|Bardeleben, Carolyne; Sharma, Sanjai; Reeve, Joseph R et al. (2013) Metabolomics identifies pyrimidine starvation as the mechanism of 5-aminoimidazole-4-carboxamide-1-?-riboside-induced apoptosis in multiple myeloma cells. Mol Cancer Ther 12:1310-21|
|Martin, Jheralyn; Masri, Janine; Cloninger, Cheri et al. (2011) Phosphomimetic substitution of heterogeneous nuclear ribonucleoprotein A1 at serine 199 abolishes AKT-dependent internal ribosome entry site-transacting factor (ITAF) function via effects on strand annealing and results in mammalian target of rapamycin co J Biol Chem 286:16402-13|