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FRISC: The Faculty Research Interests Science Comparator |
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Cell Regulation; Genetics and Development, Integrative
Biology
Michael S. Brown, M.D.
Professor of Molecular Genetics and Internal Medicine
Cell Regulation
Genetics and
Development
Integrative
Biology
Office: (214) 648-2179
FAX: (214) 648-8804
Email: mbrownmsb@aol.com
Our research is directed at unraveling the mechanism by
which the SREBP pathway regulates cholesterol metabolism at the molecular, cellular, and
whole body levels.
Sterol Regulatory Element Binding Proteins (SREBPs) are
membrane-bound bHLH-Zip transcription factors that regulate the synthesis and uptake of
cholesterol and fatty acids in animal cells. Two SREBPs, designated SREBP-1a and SREBP-2,
predominate in cultured cells. The activities of both SREBPs are regulated by the sterol
content of the cells. When cells are replete with sterols, the SREBPS remain bound to
membranes of the endoplasmic reticulum and nuclear envelope and are therefore inactive.
When cells are depleted of sterols, a two-step proteolytic process releases the active
portions of the SREBPs, which enter the nucleus and stimulate transcription of genes in
three pathways of lipid metabolism: 1) cholesterol biosynthesis (HMG CoA synthase, HMG CoA
reductase, farnesyl diphosphate synthase, squalene synthase); 2) uptake of cholesterol and
fatty acids from plasma (LDL receptor and lipoprotein lipase); and 3) fatty acid
biosynthesis (acetyl CoA carboxylase, fatty acid synthase, stearoyl CoA desaturase-1).
This feedback mechanism assures a steady supply of
cholesterol and unsaturated fatty acids, and it prevents overaccumulation. Mutant cells
with blocks in SREBP processing fail to grow in the absence of added cholesterol and
unsaturated fatty acids. Making use of these mutant cells lines, we recently cloned two
membrane-bound proteases and a membrane-bound sterol-sensing regulatory molecule that
together mediate the regulated release of SREBPs from membranes. These proteins appear to
be the key players in the pathway that controls the lipid composition of cell membranes.
Selected Publications:
Shimomura, I, Hammer, RE, Richardson, JA, Ikemoto, S,
Bashmakov, Y, Goldstein, JL and Brown, MS (1998) Insulin resistance and diabetes mellitus
in transgenic mice expressing nuclear SREBP-1c in adipose tissue: Model for congenital
generalized lipodystrophy. Genes and Development 12:3182-3194
Sakai, J, Rawson, RB, Espenshade, PJ, Cheng, D,
Seegmiller, AC, Goldstein, JL and Brown, MS (1998) Molecular identification of the
sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of
animal cells. Molecular Cell 2:505-514
Duncan, EA, Dav‚, UP, Sakai, J, Goldstein, JL and
Brown, MS (1998) Second-site cleavage in sterol regulatory element binding protein occurs
at transmembrane junction as determined by cysteine panning. J. Biol. Chem.
273:17801-17809
Rawson, RB, Zelenski, NG, Nijhawan, D, Ye, J, Sakai, J,
Hasan, MT, Chang, TY, Brown, MS and Goldstein, JL (1997) Complementation cloning of S2P, a
gene encoding a putative metalloprotease required for intramembrane cleavage of SREBP's. Molecular
Cell 1:47-57
Brown, MS and Goldstein, JL (1997) The SREBP pathway:
Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription
factor. Cell 89:331-340
Hua, X, Nohturfft, A, Goldstein, JL and Brown, MS (1996)
Sterol resistance in CHO cells traced to point mutation in SREBP Cleavage-Activating
Protein (SCAP) Cell 87:415-426
Shimano, H, Horton, JD, Hammer, RE, Shimomura, I, Brown,
MS and Goldstein, JL (1996) Overproduction of cholesterol and fatty acids causes massive
liver enlargement in transgenic mice expressing truncated SREBP-1a. J. Clin. Invest.
98:1575-1584
Sakai, J, Duncan, EA, Rawson, RB, Hua, X, Brown, MS and
Goldstein, JL (1996) Sterol-regulated release of SREBP-2 from cell membranes requires two
sequential cleavages, one within a transmembrane segment. Cell 85:1037-1046
Wang, X, Sato, R, Brown, MS, Hua, X and Goldstein, JL
(1994) SREBP-1, a membrane-bound transcription factor released by sterol-regulated
proteolysis. Cell 77:53-62
Goldstein, JL and Brown, MS (1990) Regulation of the
mevalonate pathway: Nature 343:425-430
Brown, MS and Goldstein, JL (1986) A receptor-mediated
pathway for cholesterol homeostasis. Science 232:34-47
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Last updated: 17 Nov 2000
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