Michael S(tuart) Brown - Key Papers

Biochemical geneticist, born in New York City, New York, USA. He began his close personal and professional relationship with Joseph Goldstein when the two men studied at the Massachusetts General Hospital, Boston (1966–8). Brown investigated digestive system biochemistry at the National Institutes of Health (1968–71), then joined Goldstein at the University of Texas (1971). Together they found that patients with familial hypercholesterolemia have deficient cellular binding sites for low-density lipoproteins (LDLs), and they determined the nucleotide sequence of LDL-receptor genes. For these revolutionary studies in cholesterol metabolism, they shared the 1985 Nobel Prize for Physiology or Medicine.

Key Papers

[] Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man.

[] Regulation of the activity of the low density lipoprotein receptor in human fibroblasts.

[] Release of low density lipoprotein from its cell surface receptor by sulfated glycosaminoglycans.

[] Receptor-mediated control of cholesterol metabolism.

[] Heterozygous familial hypercholesterolemia: failure of normal allele to compensate for mutant allele at a regulated genetic locus.

[] Analysis of a mutant strain of human fibroblasts with a defect in the internalization of receptor-bound low density lipoprotein.

[] Role of the coated endocytic vesicle in the uptake of receptor-bound low density lipoprotein in human fibroblasts.

[] Genetics of the LDL receptor: evidence that the mutations affecting binding and internalization are allelic.

[] A mutation that impairs the ability of lipoprotein receptors to localise in coated pits on the cell surface of human fibroblasts.

[] Immunocytochemical visualization of coated pits and vesicles in human fibroblasts: relation to low density lipoprotein receptor distribution.

[] Coated pits, coated vesicles, and receptor-mediated endocytosis. 1979 Jun 21;279(5715):679-85

[] LDL receptors in coated vesicles isolated from bovine adrenal cortex: binding sites unmasked by detergent treatment.

[] Regulation of plasma cholesterol by lipoprotein receptors.

[] Monensin interrupts the recycling of low density lipoprotein receptors in human fibroblasts.

[] Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia. 1982 Oct;30(3):715-24

[] Independent pathways for secretion of cholesterol and apolipoprotein E by macrophages.

[] Recycling receptors: the round-trip itinerary of migrant membrane proteins. 1983 Mar;32(3):663-7

[] The LDL receptor locus in familial hypercholesterolemia: multiple mutations disrupt transport and processing of a membrane receptor.

[] Depletion of intracellular potassium arrests coated pit formation and receptor-mediated endocytosis in fibroblasts. 1983 May;33(1):273-85

[] Increase in membrane cholesterol: a possible trigger for degradation of HMG CoA reductase and crystalloid endoplasmic reticulum in UT-1 cells.

[] Nucleotide sequence of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, a glycoprotein of endoplasmic reticulum.

[] Domain map of the LDL receptor: sequence homology with the epidermal growth factor precursor.

[] HMG CoA reductase: a negatively regulated gene with unusual promoter and 5' untranslated regions.

[] The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. 1984 Nov;39(1):27-38

[] Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains.

[] The LDL receptor gene: a mosaic of exons shared with different proteins.

[] Cassette of eight exons shared by genes for LDL receptor and EGF precursor. 1985 May 17;228(4701):893-895

[] Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme.

[] Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain.

[] 5' end of HMG CoA reductase gene contains sequences responsible for cholesterol-mediated inhibition of transcription.

[] Scavenger cell receptor shared.

[] A receptor-mediated pathway for cholesterol homeostasis.

[] The J.D.

[] Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit.

[] Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.

[] 42 bp element from LDL receptor gene confers end-product repression by sterols when inserted into viral TK promoter.

[] Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region. 1987 Apr 23-29;326(6115):760-765

[] Overexpression of low density lipoprotein (LDL) receptor eliminates LDL from plasma in transgenic mice.

[] Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides.

[] Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors. 1990 Nov 30;250(4985):1273-5

[] Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit.

[] cDNA cloning and expression of the peptide-binding beta subunit of rat p21ras farnesyltransferase, the counterpart of yeast DPR1/RAM1.

[] Purification of component A of Rab geranylgeranyl transferase: possible identity with the choroideremia gene product.

[] Koch's postulates for cholesterol.

[] cDNA cloning of component A of Rab geranylgeranyl transferase and demonstration of its role as a Rab escort protein. 1993 Jun 18;73(6):1091-9

[] SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene.

[] Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle.

[] SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. 1994 Apr 8;77(1):53-62

[] Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. 1996 Jun 28;85(7):1037-46

[] Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein.

[] The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.

[] Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi.

[] Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans.

[] Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes.

[] Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER.