Understanding and Targeting Cell Growth Networks in Breast Cancer
Abstract
In this final report, we describe all of the results from the five-year grant. Cancers result from an inability of a cell to control its own growth. Normally, a cell interprets external and internal signals to create a balanced growth schedule. The main interpreters of these signals within a cell are called ARF and p53, and it falls on the shoulders of these two proteins to maintain normal cell growth. In this sense, both ARF and p53 are tumor suppressors that constantly monitor the growth state of the cell. We report that loss of ARF results in tremendous gains in protein synthesis and growth. This phenotype is caused by deregulation of DDX5 and DHX33 RNA helicases. While neither DDX5 nor DHX33 are transforming oncogenes, both are required for RasV12 oncogenic transformation of cells. We also have show that ARF itself is regulated at the level of translation by the mTOR pathway. A common mechanism of translation regulation occurs through the recruitment or loss of RNA biding proteins to specific messages. Two ARF-regulated mRNAs are Drosha and NPM. Both involve proteins bound to and repressing the 3 -UTRs. Loss of ARF relieves this repression and translation of each mRNA ensues. In this manner, selective mRNA translation can be viewed as a necessary process during transformation and that the resulting proteins, while not individually oncogenic, provide activities that are required for the oncogenic phenotype. Thus, these translation pathways could be viewed as targetable moieties in the treatment of breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2013
- Accession Number
- ADA599252
Entities
People
- Jason D Weber
Organizations
- University of Washington