이진아 (University of California, Irvine)

한빛사논문

조회1,021

University of California, Irvine

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Mol. Cell, 2023 Aug 17;83(16):3010-3026.e8 | https://doi.org/10.1016/j.molcel.2023.07.017 FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1

Sungyun Cho ¹, Yujin Chun ², Long He ¹, Cuauhtemoc B. Ramirez ^2,3, Kripa S. Ganesh ⁴, Kyungjo Jeong ⁵, Junho Song ⁵, Jin Gyu Cheong ⁶, Zhongchi Li ¹, Jungmin Choi ^5,7, Joohwan Kim ², Nikos Koundouros ^1,8, Fangyuan Ding ^9,10, Noah Dephoure 8, Cholsoon Jang 3,10,11, John Blenis 1,8,12, Gina Lee ^2,10,11

¹Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA
²Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA
³Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
⁴Department of Biochemistry, Weill Cornell Medicine, Cornell University, New York, NY, USA
⁵Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, South Korea
⁶Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
⁷Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA
⁸Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA
⁹Department of Biomedical Engineering, Department of Developmental and Cell Biology, Department of Pharmaceutical Sciences, Center for Synthetic Biology, and Center for Neural Circuit Mapping, University of California Irvine, Irvine, CA, USA
¹⁰Center for Complex Biological Systems and Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
¹¹Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA
¹²Lead contact

Corresponding authors: John Blenis, Gina Lee

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis through transcription, RNA processing, and post-translational modification of metabolic enzymes. However, the mechanisms of how mTORC1 orchestrates multiple steps of gene expression programs remain unclear. Here, we identify family with sequence similarity 120A (FAM120A) as a transcription co-activator that couples transcription and splicing of de novo lipid synthesis enzymes downstream of mTORC1-serine/arginine-rich protein kinase 2 (SRPK2) signaling. The mTORC1-activated SRPK2 phosphorylates splicing factor serine/arginine-rich splicing factor 1 (SRSF1), enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging the newly transcribed lipogenic genes from RNA polymerase II to the SRSF1 and U1-70K-containing RNA-splicing machinery. This mTORC1-regulated, multi-protein complex promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth.

논문정보

형식Research article
게재일2023년 08월 (BRIC 등록일 2023-08-22)
연구진국내+국외 연구진
분야 의약학 > 분자세포의학

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