1. mTORC1 stimulates cell growth through SAM synthesis and m 6 A mRNA-dependent control of protein synthesis.
- Author
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Villa E, Sahu U, O'Hara BP, Ali ES, Helmin KA, Asara JM, Gao P, Singer BD, and Ben-Sahra I
- Subjects
- Adenosine metabolism, Animals, Base Sequence, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Cycle Proteins metabolism, Cell Proliferation, Female, HEK293 Cells, HeLa Cells, Humans, Methionine Adenosyltransferase genetics, Methionine Adenosyltransferase metabolism, Methylation, Mice, Nude, Proto-Oncogene Proteins c-myc metabolism, RNA Splicing Factors metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction, Transcription, Genetic, Mice, Adenosine analogs & derivatives, Mechanistic Target of Rapamycin Complex 1 metabolism, Protein Biosynthesis, S-Adenosylmethionine metabolism
- Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient, growth, and oncogenic signals. We found that mTORC1 stimulates the synthesis of the major methyl donor, S-adenosylmethionine (SAM), through the control of methionine adenosyltransferase 2 alpha (MAT2A) expression. The transcription factor c-MYC, downstream of mTORC1, directly binds to intron 1 of MAT2A and promotes its expression. Furthermore, mTORC1 increases the protein abundance of Wilms' tumor 1-associating protein (WTAP), the positive regulatory subunit of the human N
6 -methyladenosine (m6 A) RNA methyltransferase complex. Through the control of MAT2A and WTAP levels, mTORC1 signaling stimulates m6 A RNA modification to promote protein synthesis and cell growth. A decline in intracellular SAM levels upon MAT2A inhibition decreases m6 A RNA modification, protein synthesis rate, and tumor growth. Thus, mTORC1 adjusts m6 A RNA modification through the control of SAM and WTAP levels to prime the translation machinery for anabolic cell growth., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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