The Brown/Goldstein laboratory is unique in medical research because it has been supervised jointly by two scientists for 33 years. The laboratory is devoted to solving a fundamental problem: how do animals regulate the synthesis of cholesterol and other lipids so as to maintain constant membrane composition? Several years ago we discovered sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate genes encoding more than 30 enzymes required for lipid synthesis, uptake and storage. To reach the nucleus the SREBPs must travel to the Golgi complex where proteases release the active transcription domains. We call this the SREBP pathway. Excess cholesterol blocks SREBP movement, thus inhibiting lipid synthesis and establishing a feedback loop. Defects in SREBP regulation contribute to common diseases, ranging from heart attacks to obesity and diabetes.
RESEARCH INTERESTS
Cholesterol and Lipoprotein Metabolism
Genetics of Human Disease
RECENT PUBLICATIONS
Engelking, L.J., Evers, B.M., Richardson, J.A., Goldstein, J.L., Brown, M.S. and Liang, G., "Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin." J. Clin. Invest., 116:2356-2365, 2006
Radhakrishnan, A., Ikeda, Y., Kwon, H.J., Brown, M.S., and Goldstein, J.L., "Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig." Proc. Natl. Acad. Sci. USA, 104:6511-6518, 2007
Sun, L.-P., Seemann, J., Goldstein, J.L., and Brown, M.S., "Sterol-regulated transport of SREBPS from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins." Proc. Natl. Acad. Sci. USA, 104:6519-6526, 2007
Infante, R.E., Abi-Mosleh, L., Radhakrishnan, A., Dale, J.D., Brown, M.S., and Goldstein, J.L., "Purified NPC1 protein: I. Binding of cholesterol and oxysterols to a 1278-amino acid membrane protein." J. Biol. Chem., 283:1052-1063, 2008
Yang, J., Brown, M.S., Liang, G., Grishin, N.V., and Goldstein, J.L., "Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone." Cell, 132:387-396, 2008
SIGNIFICANT PUBLICATIONS
Brown, M.S. and Goldstein, J.L., "The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor." Cell, 89:331-340, 1997
Shimomura, I., Hammer, R.E., Ikemoto, S., Brown, M.S., and Goldstein, J.L., "Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy." Nature, 401:73-76, 1999
Yang, T., Espenshade, P.J., Wright, M.E., Yabe, D., Gong, Y., Aebersold, R., Goldstein, J.L., and Brown, M.S., "Crucial step in cholesterol homeostasis: Sterols promote binding of SCAP to INSIG-1, amembrane protein that facilitates retention of SREBPs in the ER." Cell, 110:489-500, 2002
Radhakrishnan, A., Sun, L.-P., Kwon, H.J., Brown, M.S., and Goldstein, J.L., "Direct binding of cholesterol to the purified membrane region of SCAP: Mechanism for a sterol-sensing domain." Molecular Cell, 15:259-268, 2004
Goldstein, J.L., DeBose-Boyd, R.A. and Brown, M.S., "Protein sensors for membrane sterols." Cell, 124:35-46, 2006
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