User:GoldbergAL/sandbox

Research Contributions
Alfred Goldberg is an American cell biologist-biochemist and a professor at Harvard Medical School. His many fundamental discoveries have concerned the biochemical mechanisms and physiological regulation of protein breakdown in cells. Dr. Goldberg’s interest in this process emerged from his discovery as a student that protein degradation in muscles is tightly regulated and a major determinant of muscle size. His subsequent research in bacterial and animal cells first demonstrated that all cells selectively degrade misfolded proteins by an ATP-dependent process. They then showed that such proteins in mammalian cells are degraded not by the lysosome, but by a soluble ATP-dependent system, now termed the ubiquitin-proteasome pathway. He and coworkers subsequently discovered the ATP-dependent proteases (Lon, ClpAP), a new type of enzyme that catalyzes the selective degradation of abnormal proteins in bacteria and mitochondria. His lab went on to co-discover in mammalian cells the large cellular particle that degrades ubiquitinated proteins, which he named the 26S proteasome, and clarified its relationship to its core proteolytic particle, which he named the 20S proteasome. In addition, Goldberg and colleagues have played a major role in elucidating the biochemical mechanisms of these novel enzymes and their modes of regulation in bacterial and mammalian cells.

Dr. Goldberg & collaborators also introduced the proteasome inhibitors (e.g., MG132) now used as research tools in many thousands of studies, and by founding a small biotech company (Myogenics/ProScript), he initiated the development of the proteasome inhibitor, Bortezomib/Velcade, which is now used worldwide as the standard treatment of the blood cancer, multiple myeloma. Also, of very wide impact have been Dr. Goldberg’s extensive discoveries about the cellular and transcriptional mechanisms for the excessive protein degradation that cause muscle atrophy   with disuse, fasting, and disease, about the roles of proteasomes , immunoproteasomes and amino-peptidases (ERAP1)  in antigen presentation to the immune system, and about this pathway’s role in clearing misfolded, aggregation-prone proteins as cause neurodegenerative disease. Dr. Goldberg’s various studies have advanced our understanding of many areas of biology and disease mechanisms, and have also had a major impact on bacterial protein production in industry and on medical practice.

Education & Career
Professor Goldberg graduated from Classical High School (Providence, RI) and from Harvard College in 1963, Magna Cum Laude, Phi Beta Kappa. His honor’s research in Biochemical Sciences was performed in the laboratory of Prof James Watson and Prof Walter Gilbert. He then studied physiology at Cambridge University as one of the first Churchill Scholars (1963-64). After attending Harvard Medical School (1964-1965), he earned his PhD in Physiology at Harvard for research in the laboratory of Prof HM Goodman. Goldberg was then appointed a National Research Scholar and Instructor in Physiology (1968), Assistant Professor in 1969, and full Professor of Physiology at Harvard (1977) and since 1993 has been Professor of Cell Biology. Although he has been on the faculty at Harvard Medical School his entire professional career, he also held Visiting Professorships at the University of California (Berkeley) (1976), the Pasteur Institute, Paris (1995), and as Overseas Fellow at St. Johns College, Cambridge University (2012) and has often served as an adviser in the biotech industry.

Professional Honors
Dr. Goldberg is amongst the .01% most cited authors in the life sciences and has been invited to give many keynote addresses and prize lectureships, including the McNaughton Prize Lecturer, McGill Univ (1997), Rothschild Memorial Lecturer, Israel Academy Sciences (1998), da Vinci Lecturer, Univ Milan (2002), Fay Lecturer, Univ Massachusetts (2003), Severo Ochoa Prize Lecturer, NYU (2004), Nobel Forum Lecturer, Karolinska Institute (2005), Centennial Lecturer, Biochemical Society (2006), Cristofalo Lecturer, Univ Pennsylvania (2015), Caspi Lecture, Univ Massachusetts (2015), and Benevuto Prize Lecture, MD Anderson Cancer Center (2019). International symposia honoring Dr. Goldberg’s pioneering contributions were organized by the Cachexia Society (2004) and the Chinese Academy of Science, Beijing Univ (2007) on “Ubiquitin and Protein Degradation”.

Dr. Goldberg has been awarded honorary doctorate degrees from the Watson School of Biology, Cold Spring Harbor Laboratory (2009), Maastricht University, Netherlands (2011), and University of Barcelona, Spain (2014). He has been elected to membership in the American Academy of Arts & Sciences (2004), National Academy of Medicine (2009), National Academy of Sciences (2015), and a Fellow of the American Association for the Advancement of Science (2009) and of the American Physiological Society (2015). Dr. Goldberg was awarded the Novartis-Drew University Award in Biochemical Science (with T. Maniatis & A. Varshavsky) (1998), Knobil Prize for Medical Research, Univ Texas School of Medicine (2007), Gabbay Award for Biotechnology and Medicine, Brandeis University (2008), Warren Alpert Foundation Prize (with J. Adams, K. Anderson, P. Richardson) for development of Bortezomib/Velcade (2012), Ernest Beutler Prize for Basic Science, American Society of Hematology (2015), and the Passano Prize for Medical Research (2021).

Family
Since 1970, Prof Goldberg has been married to Dr. Joan Helpern Goldberg, a physician (hematologist). They have two children, Aaron Goldberg, a well-known jazz pianist, and Julie B. Goldberg, a software engineer.

Discussions of Goldberg’s Career
Goldberg, AL. Interview. Curr Biology. 2014; 24(17): pR780–R782. doi: 10.1016/j.cub.2014.08.014

Highly Influential Publications

 * 1) Goldberg AL. Degradation of abnormal proteins in Escherichia coli (protein breakdown-protein structure-mistranslation-amino acid analogs-puromycin). Proc Natl Acad Sci U S A. 1972 Feb;69(2):422-6. PubMed PMID: 4551144; PubMed Central PMCID: PMC426471.
 * 2) Prouty WF, Goldberg AL. Fate of abnormal proteins in E. coli accumulation in intracellular granules before catabolism. Nat New Biol. 1972 Nov 29;240(100):147-50. PubMed PMID: 4565695.
 * 3) Goldberg AL, St John AC. Intracellular protein degradation in mammalian and bacterial cells: Part 2. Annu Rev Biochem. 1976;45:747-803. PubMed PMID: 786161.
 * 4) Goldberg AL and Dice JF. Intracellular protein degradation in mammalian and bacterial cells. Ann Rev Biochem 1974; 43: 835-869. PubMed PMID: 4604628.
 * 5) Goldberg AL. Protein degradation and protection against misfolded or damaged proteins. Nature. 2003 Dec 18;426(6968):895-9. PubMed PMID: 14685250.
 * 6) Etlinger JD, Goldberg AL. A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. Proc Natl Acad Sci U S A. 1977 Jan;74(1):54-8. PubMed PMID: 264694; PubMed Central PMCID: PMC393195.
 * 7) Chung CH, Goldberg AL. The product of the lon (capR) gene in Escherichia coli is the ATP-dependent protease, protease La. Proc Natl Acad Sci U S A. 1981 Aug;78(8):4931-5. PubMed PMID: 6458037; PubMed Central PMCID: PMC320299.
 * 8) Goff SA and Goldberg AL. Production of abnormal proteins in E. coli stimulates transcription of lon and other heat-shock genes. Cell 1985; 41: 587-595. PubMed PMID: 3886165.
 * 9) Waxman L, Fagan JM, Goldberg AL. Demonstration of two distinct high molecular weight proteases in rabbit reticulocytes, one of which degrades ubiquitin conjugates. J Biol Chem. 1987 Feb 25;262(6):2451-7. PubMed PMID: 3029081.
 * 10) Hwang BJ, Park WJ, Chung CH, Goldberg AL. Escherichia coli contains a soluble ATP-dependent protease (Ti) distinct from protease La. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5550-4. PubMed PMID: 3303028; PubMed Central PMCID: PMC298900.
 * 11) Gaczynska M, Rock KL, Goldberg AL. Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature. 1993 Sep 16;365(6443):264-7. PubMed PMID: 8396732.
 * 12) Rock KL, Gramm C, Rothstein L, Clark K, Stein R, et al…Goldberg AL. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994 Sep 9;78(5):761-71. PubMed PMID: 8087844.
 * 13) Goldberg AL, Gaczynska M, Grant E, Michalek M, Rock KL. Functions of the proteasome in antigen presentation. Cold Spring Harb Symp Quant Biol. 1995;60:479-90. PubMed PMID: 8824421.
 * 14) Rock KL, Goldberg AL. Degradation of cell proteins and the generation of MHC class I-presented peptides. Annu Rev Immunol. 1999; 17: 739-79
 * 15) Goldberg AL. Development of proteasome inhibitors as research tools and cancer drugs. J Cell Biol. 2012 Nov 12;199(4):583-8. PubMed PMID: 23148232; PubMed Central PMCID: PMC3494858.
 * 16) Coux O, Tanaka K, Goldberg AL. Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem. 1996;65:801-47. PubMed PMID: 8811196.
 * 17) Smith DM, Chang SC, Park S, Finley D, Cheng Y, et al. Docking of the proteasomal ATPases' carboxyl termini in the 20S proteasome's alpha ring opens the gate for substrate entry. Mol Cell. 2007 Sep 7;27(5):731-44. PubMed PMID: 17803938; PubMed Central PMCID: PMC2083707.
 * 18) Smith DM, Fraga H, Reis C, Kafri G, Goldberg AL. ATP binds to proteasomal ATPases in pairs with distinct functional effects, implying an ordered reaction cycle. Cell. 2011 Feb 18;144(4):526-38. PubMed PMID: 21335235; PubMed Central PMCID: PMC3063399.
 * 19) Mitch WE, Goldberg AL. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med. 1996 Dec 19;335(25):1897-905. PubMed PMID: 8948566.
 * 20) Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 2004 Jan;18(1):39-51. PubMed PMID: 14718385.
 * 21) Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004 Apr 30;117(3):399-412. PubMed PMID: 15109499; PubMed Central PMCID: PMC3619734.
 * 22) Cohen S, Nathan JA, Goldberg AL. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat Rev Drug Discov. 2015 Jan;14(1):58-74. PubMed PMID: 25549588.
 * 23) Lokireddy, S, Kukushkin, NV, and Goldberg, AL. cAMP-induced phosphorylation of the 26S proteasome enhances its function and the degradation of misfolded proteins. Proc Natl Acad Sci USA. 2015 Dec 29; 112(52): E716-85. Doi 10.1073. PubMed PMID: 1522332112.
 * 24) VerPlank J, Lokireddy S, Zhao J, Goldberg AL. 26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation. Proc Natl Acad Sci U S A. 2019. doi:10.1073/pnas.1809254116. PMID: 30782827.
 * 25) VerPlank JJS, Tyrkalska SD, Fleming A, Rubinsztein DC, Goldberg AL. cGMP via PKG activates 26S proteasomes and enhances degradation of proteins, including ones that cause neurodegenerative diseases. Proc Natl Acad Sci U S A. 2020;117(25):14220-14230. doi:10.1073/pnas.2003277117. PMID: 32513741.