TY - JOUR
T1 - The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation
AU - Palangat, Murali
AU - Anastasakis, Dimitrios G.
AU - Fei, Dennis Liang
AU - Lindblad, Katherine E.
AU - Bradley, Robert
AU - Hourigan, Christopher S.
AU - Hafner, Markus
AU - Larson, Daniel R.
N1 - Funding Information:
We thank Dr. Harold Varmus for support, making available cell lines, reagents, other resources, and for critical reading of the manuscript; Dr. Alan Hinnebusch, Dr. Sandra Wolin, Dr. Nicholas Guydosh, and Dr. Jeffrey Chao for critical reading of the manuscript and valuable suggestions. M.P. and D.R.L. acknowledge Dr. Heather Kalish from the Micro Analytical Immunochemistry Unit, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIH) for performing ELISA, and Katherine McKinnon and Sophia Brown from the Center for Cancer Research FACS Core Facility at NIH for support with FACS. D.L.F. acknowledges the support of Dr. Benjamin Durham, M.D., from Memorial Sloan Kettering Cancer Center for evaluation of tumor histology; Sukanya Goswami (Weill Cornell Medicine), Danielle Miller-O’Mard (National Human Genome Research Institute [NHGRI]), and members of the transgenic mouse core at NHGRI for technical assistance with the mouse experiments. This work was supported in part by the Intramural Research Programs of the National Cancer Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health.
Funding Information:
We thank Dr. Harold Varmus for support, making available cell lines, reagents, other resources, and for critical reading of the manuscript; Dr. Alan Hinnebusch, Dr. Sandra Wolin, Dr. Nicholas Guydosh, and Dr. Jeffrey Chao for critical reading of the manuscript and valuable suggestions. M.P. and D.R.L. acknowledge Dr. Heather Kalish from the Micro Analytical Immunochemistry Unit, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIH) for performing ELISA, and Katherine McKinnon and Sophia Brown from the Center for Cancer Research FACS Core Facility at NIH for support with FACS. D.L.F. acknowledges the support of Dr. Benjamin Durham, M.D., from Memorial Sloan Kettering Cancer Center for evaluation of tumor histology; Sukanya Goswami (Weill Cornell Medi-cine), Danielle Miller-O’Mard (National Human Genome Research Institute [NHGRI]), and members of the transgenic mouse core at NHGRI for technical assistance with the mouse experiments. This work was supported in part by the Intramural Research Programs of the National Cancer Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health.
Publisher Copyright:
© 2019 Palangat et al.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
KW - IL8
KW - Myeloid leukemia
KW - Splicing factor mutations
KW - Translation regulator
KW - U2AF1
UR - http://www.scopus.com/inward/record.url?scp=85065510567&partnerID=8YFLogxK
U2 - 10.1101/gad.319590.118
DO - 10.1101/gad.319590.118
M3 - Article
C2 - 30842218
AN - SCOPUS:85065510567
VL - 33
SP - 482
EP - 497
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 9-10
ER -