Integrative Profiling of Alternative Splicing Induced by U2AF1 S34F Mutation in Lung Adenocarcinoma Reveals a Mechanistic Link to Mitotic Stress
- 주제(키워드) alternative splicing , lung adenocarcinoma , mitotic stress , S34F , U2AF1
- 주제(기타) Biochemistry & Molecular Biology; Cell Biology
- 설명문(일반) [Kim, Suyeon; Jun, Yukyung; Lee, Sanghyuk; Jung, Yeonjoo; Kim, Jaesang] Ewha Res Ctr Syst Biol, Seoul 03760, South Korea; [Kim, Suyeon; Jun, Yukyung; Lee, Sanghyuk; Jung, Yeonjoo; Kim, Jaesang] Ewha Womans Univ, Dept Life Sci, Seoul 03760, South Korea; [Park, Charny] Natl Canc Ctr, Res Inst, Goyang 10408, South Korea
- 발행기관 KOREAN SOC MOLECULAR & CELLULAR BIOLOGY
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000155685
- 본문언어 영어
- Published As http://dx.doi.org/10.14348/molcells.2018.0176
- 저작권 이화여자대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Mutations in spliceosome components have been implicated in carcinogenesis of various types of cancer. One of the most frequently found is U2AF1 S34F missense mutation. Functional analyses of this mutation have been largely limited to hematological malignancies although the mutation is also frequently seen in other cancer types including lung adenocarcinoma (LUAD). We examined the impact of knockdown (KD) of wild type (wt) U2AF1 and ectopic expression of two splice variant S34F mutant proteins in terms of alternative splicing (AS) pattern and cell cycle progression in A549 lung cancer cells. We demonstrate that induction of distinct AS events and disruption of mitosis at distinct sub-stages result from KD and ectopic expression of the mutant proteins. Importantly, when compared with the splicing pattern seen in LUAD patients with U2AF1 S34F mutation, ectopic expression of S34F mutants but not KD was shown to result in common AS events in several genes involved in cell cycle progression. Our study thus points to an active role of U2AF1 S34F mutant protein in inducing cell cycle dysregulation and mitotic stress. In addition, alternatively spliced genes which we describe here may represent novel potential markers of lung cancer development.
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