RNA-binding proteins (RBPs) play a major role in RNA metabolism, and regulate diverse functions related to the processing and stability of RNA transcripts, including RNA splicing, transport, translation, and degradation. Recently, frequent mutations in the RNA-binding motif protein 10 (RBM10) were identified in human lung adenocarcinoma. However, like many RBPs, much remains unknown about RBM10 function. It is hypothesized that RBM10 may restrain phenotypes related to tumor growth and act as a novel tumor suppressor. This proposal outlines a comprehensive and detailed plan to characterize RBM10 using a combination of in vitro and in vivo approaches. Transcripts that interact and co-purify with RBM10 will be sequenced and effects of RBM10 loss-of-function on RNA splicing will be examined. To investigate a potential role for RBM10 in regulating cellular phenotypes associated with tumorigenesis, overexpression and loss-of- function studies will be carried out with analyses of specific effects on cellular proliferation, apoptosis, and oncogene-induced senescence. To validate whether RBM10 is a bona fide tumor suppressor gene, Rbm10 will be deleted in cells of the mouse lung with and without concurrent activation of oncogenic KrasG12D, and effects on tumorigenesis will be assessed. The proposed research plan has the potential to improve our understanding of how disruptions to normal RNA processing can contribute to human cancer and may yield new targets for therapeutic intervention.
Recent advances in DNA sequencing technology have enabled large-scale surveys of the genetics of human cancer. However, this wealth of information has also revealed the many deficiencies that currently exist in our functional knowledge of candidate cancer-associated genes. This proposal focuses on a novel tumor suppressor gene recently identified in lung cancer, and through detailed functional analyses, aims to both expand our understanding of the processes that drive human cancer and accelerate the discovery of new targets for therapeutic intervention.
| Zhang, Xiaoyang; Choi, Peter S; Francis, Joshua M et al. (2016) Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat Genet 48:176-82 |
