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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132778-02
Application #
7883554
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Howcroft, Thomas K
Project Start
2008-07-01
Project End
2014-05-31
Budget Start
2010-06-08
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$273,159
Indirect Cost
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073