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Joseph L. Goldstein

Joseph L. Goldstein
Born April 18, 1940 (1940-04-18) (age 69)
Kingstree, South Carolina
Fields biochemistry
Known for cholesterol
Notable awards Nobel Prize in Physiology or Medicine (1985)

Joseph L. Goldstein (born April 18, 1940) from Kingstree, South Carolina is a Nobel Prize winning biochemist and geneticist, and a pioneer in the study of cholesterol metabolism.

Contents

Biography

Dr. Goldstein received a BS in chemistry from Washington and Lee University in 1962 and his M.D. from the University of Texas Southwestern Medical Center in 1966. In 1985 he received the Nobel Prize in Physiology or Medicine (together with Michael S. Brown) for his research on the metabolism of low density lipoprotein (LDL), and has won numerous other awards for his contributions related to genetic diseases.

Returning to the University of Texas Health Science Center in Dallas in 1972 (now called UT Southwestern Medical Center) Goldstein and his close colleague Brown researched cholesterol metabolism and discovered that human cells have low-density lipoprotein (LDL) receptors that extract cholesterol from the bloodstream. The lack of sufficient LDL receptors is the cause of familial hypercholesterolemia, which predisposes heavily for cholesterol-related diseases. In addition to explaining the underlying pathology of the widely-observed link between high levels of circulating cholesterol as LDL and coronary artery disease, their work uncovered a previously-unappreciated, yet fundamental, aspect of cell biology - Receptor-mediated endocytosis.

In addition to contributing fundamentally to our understanding of how the cells in our bodies work, Drs. Goldstein and Brown's findings led to the development of statin drugs, the cholesterol-lowering compounds that today are used by 16 million Americans and are the most widely prescribed medications in the United States. This crucial discovery is improving more lives every year. New federal cholesterol guidelines are expected to triple the number of Americans taking statin drugs to lower their cholesterol, reducing the risk of heart disease and stroke for countless people. Subsequently the team lead by Drs. Brown and Goldstein elucidated the role of lipid modification of proteins (protein prenylation) in cancer.

In 1993, their postdoctoral trainees Wang Xiaodong and Michael Briggs purified the Sterol Regulatory Element-Binding Proteins (SREBPs), a family of membrane-bound transcription factors. Since 1993, Drs. Goldstein, Brown, and their colleagues have described the unexpectedly complex machinery that proteolytically releases the SREBPs from membranes, thus allowing their migration to the nucleus where they activate all the genes involved in the synthesis of cholesterol and fatty acids. The machinery for generating active SREBPs is tightly regulated by a negative feedback mechanism, which explains how cells maintain the necessary levels of fats and cholesterol in the face of varying environmental circumstances.

Goldstein is a Regental Professor of the University of Texas Southwestern Medical Center at Dallas, holds the Julie and Louis A. Beecherl Distinguished Chair in Biomedical Science, and the Paul J. Thomas Chair in Medicine. Frequently mentioned as a candidate for nationally-prominent positions in scientific administration, Goldstein, like his colleague Michael S. Brown, elects to continue hands-on involvement with research. Together, they lead a research team that typically includes a dozen doctoral and postdoctoral trainees. He and his colleague are among the most highly cited scientists in the world. For a look at Goldstein's current research, check out the Brown and Goldstein Lab home.

Goldstein currently serves as Chairman of the Albert Lasker Medical Research Awards Jury and is a member of the Boards of Trustees of the Howard Hughes Medical Institute and The Rockefeller University. He is also a member of the U.S. National Academy of Sciences and a Foreign Member of The Royal Society.

Awards

Key Papers

  • Goldstein JL, Brown MS (October 1973). "Familial hypercholesterolemia: Identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol". Proc. Natl. Acad. Sci. USA 70 (10): 2804–8. doi:10.1073/pnas.70.10.2804. PMID 4355366.  
  • Brown MS, Goldstein JL (March 1974). "Familial hypercholesterolemia: Defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity". Proc. Natl. Acad. Sci. USA 71 (3): 788–92. doi:10.1073/pnas.71.3.788. PMID 4362634.  
  • Brown MS, Goldstein JL (July 1974). "Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man". Science 185 (4145): 61–3. doi:10.1126/science.185.4145.61. PMID 4366052.  
  • Goldstein JL, Brown MS (August 1974). "Binding and degradation of low density lipoproteins by cultured human fibroblasts: Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia". J. Biol. Chem. 249 (16): 5153–62. PMID 4368448. http://www.ncbi.nlm.nih.gov/pubmed/4368448?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=7.  
  • Brown MS, Goldstein JL (November 1975). "Regulation of the activity of the low density lipoprotein receptor in human fibroblasts". Cell 6 (3): 307–16. doi:10.1016/0092-8674(75)90182-8. PMID 212203.  
  • Goldstein JL, Basu SK, Brunschede GY, Brown MS (January 1976). "Release of low density lipoprotein from its cell surface receptor by sulfated glycosaminoglycans". Cell 7 (1): 85–95. doi:10.1016/0092-8674(76)90258-0. PMID 181140.  
  • Brown MS, Goldstein JL (January 1976). "Receptor-mediated control of cholesterol metabolism". Science 191 (4223): 150–4. doi:10.1126/science.174194. PMID 174194.  
  • Goldstein JL, Sobhani MK, Faust JR, Brown MS (October 1976). "Heterozygous familial hypercholesterolemia: failure of normal allele to compensate for mutant allele at a regulated genetic locus". Cell 9 (2): 195–203. doi:10.1016/0092-8674(76)90110-0. PMID 184960.  
  • Brown MS, Goldstein JL (December 1976). "Analysis of a mutant strain of human fibroblasts with a defect in the internalization of receptor-bound low density lipoprotein". Cell 9 (4 PT 2): 663–74. doi:10.1016/0092-8674(76)90130-6. PMID 189940.  
  • Anderson RG, Brown MS, Goldstein JL (March 1977). "Role of the coated endocytic vesicle in the uptake of receptor-bound low density lipoprotein in human fibroblasts". Cell 10 (3): 351–64. doi:10.1016/0092-8674(77)90022-8. PMID 191195.  
  • Goldstein JL, Brown MS, Stone NJ (November 1977). "Genetics of the LDL receptor: evidence that the mutations affecting binding and internalization are allelic". Cell 12 (3): 629–41. doi:10.1016/0092-8674(77)90263-X. PMID 200368.  
  • Anderson RG, Goldstein JL, Brown MS (1977). "A mutation that impairs the ability of lipoprotein receptors to localise in coated pits on the cell surface of human fibroblasts". Nature 270 (5639): 695–9. doi:10.1038/270695a0. PMID 201867.  
  • Anderson RG, Vasile E, Mello RJ, Brown MS, Goldstein JL (November 1978). "Immunocytochemical visualization of coated pits and vesicles in human fibroblasts: relation to low density lipoprotein receptor distribution". Cell 15 (3): 919–33. doi:10.1016/0092-8674(78)90276-3. PMID 215316.  
  • Goldstein JL, Anderson RG, Brown MS (June 1979). "Coated pits, coated vesicles, and receptor-mediated endocytosis". Nature 279 (5715): 679–85. doi:10.1038/279679a0. PMID 221835.  
  • Mello RJ, Brown MS, Goldstein JL, Anderson RG (July 1980). "LDL receptors in coated vesicles isolated from bovine adrenal cortex: binding sites unmasked by detergent treatment". Cell 20 (3): 829–37. doi:10.1016/0092-8674(80)90329-3. PMID 6251975.  
  • Brown MS, Kovanen PT, Goldstein JL (May 1981). "Regulation of plasma cholesterol by lipoprotein receptors". Science 212 (4495): 628–35. doi:10.1126/science.6261329. PMID 6261329.  
  • Basu SK, Goldstein JL, Anderson RG, Brown MS (May 1981). "Monensin interrupts the recycling of low density lipoprotein receptors in human fibroblasts". Cell 24 (2): 493–502. doi:10.1016/0092-8674(81)90340-8. PMID 6263497.  
  • Tolleshaug H, Goldstein JL, Schneider WJ, Brown MS (October 1982). "Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia". Cell 30 (3): 715–24. doi:10.1016/0092-8674(82)90276-8. PMID 6291781.  
  • Basu SK, Goldstein JL, Brown MS (February 1983). "Independent pathways for secretion of cholesterol and apolipoprotein E by macrophages". Science 219 (4586): 871–3. doi:10.1126/science.6823554. PMID 6823554.  
  • Brown MS, Anderson RG, Goldstein JL (March 1983). "Recycling receptors: the round-trip itinerary of migrant membrane proteins". Cell 32 (3): 663–7. doi:10.1016/0092-8674(83)90052-1. PMID 6299572.  
  • Tolleshaug H, Hobgood KK, Brown MS, Goldstein JL (March 1983). "The LDL receptor locus in familial hypercholesterolemia: multiple mutations disrupt transport and processing of a membrane receptor". Cell 32 (3): 941–51. doi:10.1016/0092-8674(83)90079-X. PMID 6299582.  
  • Larkin JM, Brown MS, Goldstein JL, Anderson RG (May 1983). "Depletion of intracellular potassium arrests coated pit formation and receptor-mediated endocytosis in fibroblasts". Cell 33 (1): 273–85. doi:10.1016/0092-8674(83)90356-2. PMID 6147196.  
  • Orci L, Brown MS, Goldstein JL, Garcia-Segura LM, Anderson RG (April 1984). "Increase in membrane cholesterol: a possible trigger for degradation of HMG CoA reductase and crystalloid endoplasmic reticulum in UT-1 cells". Cell 36 (4): 835–45. doi:10.1016/0092-8674(84)90033-3. PMID 6705048.  
  • Chin DJ, Gil G, Russell DW, et al. (1984). "Nucleotide sequence of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, a glycoprotein of endoplasmic reticulum". Nature 308 (5960): 613–7. doi:10.1038/308613a0. PMID 6546784.  
  • Russell DW, Schneider WJ, Yamamoto T, Luskey KL, Brown MS, Goldstein JL (June 1984). "Domain map of the LDL receptor: sequence homology with the epidermal growth factor precursor". Cell 37 (2): 577–85. doi:10.1016/0092-8674(84)90388-X. PMID 6327078.  
  • Reynolds GA, Basu SK, Osborne TF, et al. (August 1984). "HMG CoA reductase: a negatively regulated gene with unusual promoter and 5' untranslated regions". Cell 38 (1): 275–85. doi:10.1016/0092-8674(84)90549-X. PMID 6088070.  
  • Yamamoto T, Davis CG, Brown MS, et al. (November 1984). "The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA". Cell 39 (1): 27–38. doi:10.1016/0092-8674(84)90188-0. PMID 6091915.  
  • Lehrman MA, Schneider WJ, Südhof TC, Brown MS, Goldstein JL, Russell DW (January 1985). "Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains". Science 227 (4683): 140–6. doi:10.1126/science.3155573. PMID 3155573.  
  • Südhof TC, Goldstein JL, Brown MS, Russell DW (May 1985). "The LDL receptor gene: a mosaic of exons shared with different proteins". Science 228 (4701): 815–22. doi:10.1126/science.2988123. PMID 2988123.  
  • Südhof TC, Russell DW, Goldstein JL, Brown MS, Sanchez-Pescador R, Bell GI (May 1985). "Cassette of eight exons shared by genes for LDL receptor and EGF precursor". Science 228 (4701): 893–5. doi:10.1126/science.3873704. PMID 3873704.  
  • Gil G, Faust JR, Chin DJ, Goldstein JL, Brown MS (May 1985). "Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme". Cell 41 (1): 249–58. doi:10.1016/0092-8674(85)90078-9. PMID 3995584.  
  • Lehrman MA, Goldstein JL, Brown MS, Russell DW, Schneider WJ (July 1985). "Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain". Cell 41 (3): 735–43. doi:10.1016/S0092-8674(85)80054-4. PMID 3924410.  
  • Osborne TF, Goldstein JL, Brown MS (August 1985). "5' end of HMG CoA reductase gene contains sequences responsible for cholesterol-mediated inhibition of transcription". Cell 42 (1): 203–12. doi:10.1016/S0092-8674(85)80116-1. PMID 3860301.  
  • Brown MS, Goldstein JL (1985). "Scavenger cell receptor shared". Nature 316 (6030): 680–1. doi:10.1038/316680a0. PMID 4033768.  
  • Brown MS, Goldstein JL (April 1986). "A receptor-mediated pathway for cholesterol homeostasis". Science 232 (4746): 34–47. doi:10.1126/science.3513311. PMID 3513311.  
  • Davis CG, Lehrman MA, Russell DW, Anderson RG, Brown MS, Goldstein JL (April 1986). "The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors". Cell 45 (1): 15–24. doi:10.1016/0092-8674(86)90533-7. PMID 3955657.  
  • Yamamoto T, Bishop RW, Brown MS, Goldstein JL, Russell DW (June 1986). "Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit". Science 232 (4755): 1230–7. doi:10.1126/science.3010466. PMID 3010466.  
  • Lehrman MA, Goldstein JL, Russell DW, Brown MS (March 1987). "Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia". Cell 48 (5): 827–35. doi:10.1016/0092-8674(87)90079-1. PMID 3815525.  
  • Südhof TC, Russell DW, Brown MS, Goldstein JL (March 1987). "42 bp element from LDL receptor gene confers end-product repression by sterols when inserted into viral TK promoter". Cell 48 (6): 1061–9. doi:10.1016/0092-8674(87)90713-6. PMID 3030558.  
  • Davis CG, Goldstein JL, Südhof TC, Anderson RG, Russell DW, Brown MS (1987). "Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region". Nature 326 (6115): 760–5. doi:10.1038/326760a0. PMID 3494949.  
  • Hofmann SL, Russell DW, Brown MS, Goldstein JL, Hammer RE (March 1988). "Overexpression of low density lipoprotein (LDL) receptor eliminates LDL from plasma in transgenic mice". Science 239 (4845): 1277–81. doi:10.1126/science.3344433. PMID 3344433.  
  • Reiss Y, Goldstein JL, Seabra MC, Casey PJ, Brown MS (July 1990). "Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides". Cell 62 (1): 81–8. doi:10.1016/0092-8674(90)90242-7. PMID 2194674.  
  • Yokode M, Hammer RE, Ishibashi S, Brown MS, Goldstein JL (November 1990). "Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors". Science 250 (4985): 1273–5. doi:10.1126/science.2244210. PMID 2244210.  
  • Seabra MC, Reiss Y, Casey PJ, Brown MS, Goldstein JL (May 1991). "Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit". Cell 65 (3): 429–34. doi:10.1016/0092-8674(91)90460-G. PMID 2018975.  
  • Chen WJ, Andres DA, Goldstein JL, Russell DW, Brown MS (July 1991). "cDNA cloning and expression of the peptide-binding beta subunit of rat p21ras farnesyltransferase, the counterpart of yeast DPR1/RAM1". Cell 66 (2): 327–34. doi:10.1016/0092-8674(91)90622-6. PMID 1855253.  
  • Seabra MC, Brown MS, Slaughter CA, Südhof TC, Goldstein JL (September 1992). "Purification of component A of Rab geranylgeranyl transferase: possible identity with the choroideremia gene product". Cell 70 (6): 1049–57. doi:10.1016/0092-8674(92)90253-9. PMID 1525821.  
  • Brown MS, Goldstein JL (October 1992). "Koch's postulates for cholesterol". Cell 71 (2): 187–8. doi:10.1016/0092-8674(92)90346-E. PMID 1423585.  
  • Andres DA, Seabra MC, Brown MS, et al. (June 1993). "cDNA cloning of component A of Rab geranylgeranyl transferase and demonstration of its role as a Rab escort protein". Cell 73 (6): 1091–9. doi:10.1016/0092-8674(93)90639-8. PMID 8513495.  
  • Yokoyama C, Wang X, Briggs MR, et al. (October 1993). "SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene". Cell 75 (1): 187–97. PMID 8402897. http://www.ncbi.nlm.nih.gov/pubmed/8402897?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2.  
  • Garcia CK, Goldstein JL, Pathak RK, Anderson RG, Brown MS (March 1994). "Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle". Cell 76 (5): 865–73. doi:10.1016/0092-8674(94)90361-1. PMID 8124722.  
  • Wang X, Sato R, Brown MS, Hua X, Goldstein JL (April 1994). "SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis". Cell 77 (1): 53–62. doi:10.1016/0092-8674(94)90234-8. PMID 8156598.  
  • Sakai J, Duncan EA, Rawson RB, Hua X, Brown MS, Goldstein JL (June 1996). "Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment". Cell 85 (7): 1037–46. doi:10.1016/S0092-8674(00)81304-5. PMID 8674110.  
  • Hua X, Nohturfft A, Goldstein JL, Brown MS (November 1996). "Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein". Cell 87 (3): 415–26. doi:10.1016/S0092-8674(00)81362-8. PMID 8898195.  
  • Brown MS, Goldstein JL (May 1997). "The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor". Cell 89 (3): 331–40. doi:10.1016/S0092-8674(00)80213-5. PMID 9150132.  
  • DeBose-Boyd RA, Brown MS, Li WP, Nohturfft A, Goldstein JL, Espenshade PJ (December 1999). "Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi". Cell 99 (7): 703–12. doi:10.1016/S0092-8674(00)81668-2. PMID 10619424.  
  • Brown MS, Ye J, Rawson RB, Goldstein JL (February 2000). "Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans". Cell 100 (4): 391–8. doi:10.1016/S0092-8674(00)80675-3. PMID 10693756.  
  • Nohturfft A, Yabe D, Goldstein JL, Brown MS, Espenshade PJ (August 2000). "Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes". Cell 102 (3): 315–23. doi:10.1016/S0092-8674(00)00037-4. PMID 10975522.  
  • Yang T, Espenshade PJ, Wright ME, et al. (August 2002). "Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER". Cell 110 (4): 489–500. doi:10.1016/S0092-8674(02)00872-3. PMID 12202038.  
  • Goldstein JL, Brown MS (April 2009). "History of discovery: The LDL receptor". Arterioscler. Thromb. Vasc. Biol. 29 (4): 431–8. doi:10.1161/ATVBAHA.108.179564. PMID 19299327.  
  • Brown MS, Goldstein JL (April 2009). "Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL". J. Lipid Res. 50: S15–S27. doi:10.1194/jlr.R800054-JLR200. PMID 18974038.  

See also

External links

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