SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth

Porstmann, Thomas; Santos, Claudio R.; Griffiths, Beatrice; Cully, Megan; Wu, Mary; Leevers, Sally; Griffiths, John R.; Chung, Yuen-Li; Schulze, Almut

doi:10.1016/j.cmet.2008.07.007

Cited by 1,413PI3K/AKT/mTOR signaling in cancerCancer, Lipids, and MetabolismLipid metabolism and biosynthesis

SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth

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Porstmann, Thomas, Santos, Claudio R., Griffiths, Beatrice, Cully, Megan, Wu, Mary, Leevers, Sally, Griffiths, John R., Chung, Yuen-Li +1 more·2008·Cell Metabolism

DOI 10.1016/j.cmet.2008.07.007PMC PMC2593919

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Abstract

Cell growth (accumulation of mass) needs to be coordinated with metabolic processes that are required for the synthesis of macromolecules. The PI3-kinase/Akt signaling pathway induces cell growth via activation of complex 1 of the target of rapamycin (TORC1). Here we show that Akt-dependent lipogenesis requires mTORC1 activity. Furthermore, nuclear accumulation of the mature form of the sterol responsive element binding protein (SREBP1) and expression of SREBP target genes was blocked by the mTORC1 inhibitor rapamycin. We also show that silencing of SREBP blocks Akt-dependent lipogenesis and attenuates the increase in cell size in response to Akt activation in vitro. Silencing of dSREBP in flies caused a reduction in cell and organ size and blocked the induction of cell growth by dPI3K. Our results suggest that the PI3K/Akt/TOR pathway regulates protein and lipid biosynthesis in an orchestrated manner and that both processes are required for cell growth.

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SREBP-1 expression and/or activity are regulated by PI3K/Akt signaling through mTORC1 in hepatocytes, mouse embryonic fibroblasts and Drosophila.
“SREBP-1 expression and/or activity are regulated by PI3K/Akt signaling through mTORC1 in hepatocytes (61), mouse embryonic fibroblasts (62) and in Drosphila (63).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [63]
For the Drosophila portion of the citing sentence, the Results section (“SREBP Is a Target of the PI3K Pathway in Drosophila”) reports that PI3K/Akt signaling activates dSREBP function. But the Discussion says it remains to be investigated whether dSREBP regulation downstream of PI3K requires TOR, so the claimed mTORC1 link in flies is not established by this paper. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Cell growth downstream of PI3K/Akt/mTOR requires induction of de novo lipid synthesis via mTOR, due in part to increased nuclear localization of SREBP, which activates expression of lipogenic enzymes.
“Cell growth downstream of this pathway requires the induction of de novo lipid synthesis via mTOR, and this effect is due in part to increased nuclear localization of sterol regulatory element-binding protein (SREBP), a basic helix-loop-helix leucine zipper transcription factor that activates expression of a suite of lipogenic enzymes (Porstmann et al., 2008).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Porstmann et al., 2008

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Authors: Porstmann, T., Santos, C. R., Griffiths, B., Cully, M., Wu, M., Leevers, S., Griffiths, J. R., Chung, Y.-L., & Schulze, A.
Affiliations: The Honourable Society of Lincoln's Inn (GB)
Cancer Research UK (GB)
Institute of Cancer Research (GB)
Corresponding author: Schulze, Almut
ORCID: Griffiths, Beatrice
Cully, Megan
Wu, Mary
Griffiths, John R.
Chung, Yuen-Li
Schulze, Almut
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2008-09
Volume: 8
Issue: 3
Pages: 224-236
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2008.07.007
PMC: PMC2593919
OpenAlex: W2056040807
Cited by: 1,413
References: 58
Citations by year: 2026: 65 · 2025: 90 · 2024: 95 · 2023: 98 · 2022: 110 · 2021: 109 · 2020: 114 · 2019: 87 · 2018: 84 · 2017: 79 · 2016: 92 · 2015: 74 · 2014: 57 · 2013: 58 · 2012: 67
FWCI: 18.36
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by-nc-nd/3.0/ (vor, 1779 d)
Locations: Cell Metabolism (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: Cancer Research UK
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords: SREBP1, mTORC1, Akt signaling, PI3K/Akt signaling, lipogenesis, cell growth, rapamycin, cell size, protein synthesis, Drosophila, SREBP
MeSH terms: Animals, Cell Nucleus, Cells, Cultured, Drosophila, Lipids, Transcription Factors, Signal Transduction, Gene Expression, Sirolimus, Drosophila Proteins, RNA Interference, Cell Enlargement, Proto-Oncogene Proteins c-akt, Sterol Regulatory Element Binding Protein 1

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SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth

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