期刊
GENES & DEVELOPMENT
卷 33, 期 9-10, 页码 482-497出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.319590.118
关键词
IL8; U2AF1; myeloid leukemia; splicing factor mutations; translation regulator
资金
- Memorial Sloan Kettering Cancer Center
- Weill Cornell Medicine
- National Human Genome Research Institute [NHGRI]
- Intramural Research Programs of the National Cancer Institute
- National Heart, Lung, and Blood Institute of the National Institutes of Health
- NATIONAL CANCER INSTITUTE [ZIABC011383, ZIABC005450] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006163] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [ZIAAR041206, ZIAAR041201, ZIAAR041205] Funding Source: NIH RePORTER
Somatic mutations in the genes encoding components of the spliceosome occur frequently in human neoplasms, including myeloid dysplasias and leukemias, and less often in solid tumors. One of the affected factors, U2AF1, is involved in splice site selection, and the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3' splice site, and alternative splicing of many mRNAs. However, the role that this mutation plays in oncogenesis is still unknown. Here, we uncovered a noncanonical function of U2AF1, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation. This splicing-independent role of U2AF1 is altered by the S34F mutation, and polysome profiling indicates that the mutation affects translation of hundreds of mRNA. One functional consequence is increased synthesis of the secreted chemokine interleukin 8, which contributes to metastasis, inflammation, and cancer progression in mice and humans.
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