Hyperphosphorylation Regulates the Activity of SREBP1 during Mitosis
The sterol regulatory element-binding protein (SREBP) family of transcription factors controls the biosynthesis of cholesterol and other lipids, and lipid synthesis is critical for cell growth and proliferation. We were, therefore, interested in the expression and activity of SREBPs during the cell...
Saved in:
Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 33; pp. 11681 - 11686 |
---|---|
Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
16.08.2005
National Acad Sciences |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | The sterol regulatory element-binding protein (SREBP) family of transcription factors controls the biosynthesis of cholesterol and other lipids, and lipid synthesis is critical for cell growth and proliferation. We were, therefore, interested in the expression and activity of SREBPs during the cell cycle. We found that the expression of a number of SREBP-responsive promoter-reporter genes were induced in a SREBP-dependent manner in cells arrested in G2/ M. In addition, the mature forms of SREBP1a and SREBP1c were hyperphosphorylated in mitotic cells, giving rise to a phospho-epitope recognized by the mitotic protein monoclonal-2 (MPM-2) antibody. In contrast, SREBP2 was not hyperphosphorylated in mitotic cells and was not recognized by the MPM-2 antibody. The MPM-2 epitope was mapped to the C terminus of mature SREBP1, and the mitosis-specific hyperphosphorylation of SREBP1 depended on this domain of the protein. The transcriptional and DNA-binding activity of SREBP1 was enhanced in cells arrested in G2/ M, and these effects depended on the C-terminal domain of the protein. In part, these effects could be explained by our observation that mature SREBP1 was stabilized in G2/ M. In agreement with these observations, we found that the synthesis of cholesterol was increased in G2/ M-arrested cells. Thus, our results demonstrate that the activity of mature SREBP1 is regulated by phosphorylation during the cell cycle, suggesting that SREBP1 may provide a link between lipid synthesis, proliferation, and cell growth. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Abbreviations: SREBP, sterol regulatory element-binding protein; MPM-2, mitotic protein monoclonal-2; FAS, fatty acid synthase; LDLr, low-density lipoprotein receptor; FPPS, farnesyl diphosphate synthase; HMG, 3-hydroxy-3-methylglutaryl; DBD, DNA-binding domain; TAD, transactivation domain. Edited by Michael S. Brown, University of Texas Southwestern Medical Center, Dallas, TX, and approved June 29, 2005 This paper was submitted directly (Track II) to the PNAS office. Author contributions: M.T.B.-A. and J.E. designed research; M.T.B.-A., T.P., and J.E. performed research; M.T.B.-A., T.P., and J.E. analyzed data; and M.T.B.-A. and J.E. wrote the paper. To whom correspondence should be addressed. E-mail: johan.ericsson@licr.uu.se. |
ISSN: | 0027-8424 1091-6490 1091-6490 |
DOI: | 10.1073/pnas.0501494102 |