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 CNS malignancies. 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. Glioma 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 glioma cell resistance whe treatment with mTOR inhibitors is attempted.
The project details the mechanisms by which glioma tumor cells become resistant to promising new therapeutic agents called mTOR inhibitors. The mechanisms of cell intrinsic resistance to these compounds will be investigated, as well as, the pre-clinical evaluation of combination targeted therapies in glioma in vitro and in vivo models.
|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|
|VanderWall, Kristina; Daniels-Wells, Tracy R; Penichet, Manuel et al. (2013) Iron in multiple myeloma. Crit Rev Oncog 18:449-61|
|Bashir, Tariq; Cloninger, Cheri; Artinian, Nicholas et al. (2012) Conditional astroglial Rictor overexpression induces malignant glioma in mice. PLoS One 7:e47741|
|Hoang, Bao; Benavides, Angelica; Shi, Yijiang et al. (2012) The PP242 mammalian target of rapamycin (mTOR) inhibitor activates extracellular signal-regulated kinase (ERK) in multiple myeloma cells via a target of rapamycin complex 1 (TORC1)/eukaryotic translation initiation factor 4E (eIF-4E)/RAF pathway and activ J Biol Chem 287:21796-805|
|Holmes, Brent; Artinian, Nicholas; Anderson, Lauren et al. (2012) Protor-2 interacts with tristetraprolin to regulate mRNA stability during stress. Cell Signal 24:309-15|
|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|
|Shi, Yijiang; Frost, Patrick; Hoang, Bao et al. (2011) IL-6-induced enhancement of c-Myc translation in multiple myeloma cells: critical role of cytoplasmic localization of the rna-binding protein hnRNP A1. J Biol Chem 286:67-78|
|Vartanian, Raffi; Masri, Janine; Martin, Jheralyn et al. (2011) AP-1 regulates cyclin D1 and c-MYC transcription in an AKT-dependent manner in response to mTOR inhibition: role of AIP4/Itch-mediated JUNB degradation. Mol Cancer Res 9:115-30|
|Cloninger, Cheri; Bernath, Andrew; Bashir, Tariq et al. (2011) Inhibition of SAPK2/p38 enhances sensitivity to mTORC1 inhibition by blocking IRES-mediated translation initiation in glioblastoma. Mol Cancer Ther 10:2244-56|
|Hoang, Bao; Frost, Patrick; Shi, Yijiang et al. (2010) Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood 116:4560-8|
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