Photo of Alfred L. Goldberg,  PhD

Alfred L. Goldberg, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-1855
Fax: (617) 232-0173


alfred_goldberg@hms.harvard.edu

Alfred L. Goldberg, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Professor, Cell Biology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our laboratory studies the physiological regulation and molecular mechanisms of protein breakdown by the ubiquitin proteasome pathway in eukaryotic cells. A major focus is to elucidate the functioning of the 26S proteasome and especially the role of its regulatory ATPases in selectively delivering protein substrates to the 20S proteasome where they are degraded. One particular cancer-related interest is in the development of agents that block functioning of this pathway and may be useful in the clinic (e.g. Bortezomib, now used in treatment of Multiple Myeloma). Additional research efforts are focusing on the role of the ubiquitin proteasome pathway in disease states. A major goal is to understand the mechanism of how overall proteolysis in muscle is accelerated and causes muscle atrophy in various disease states (e.g. cancer cachexia). We are also attempting to understand the role of protein breakdown in immune surveillance (the role of the proteasome in generating MHC Class I antigenic peptides) and how cells selectively degrade misfolded protein as arise in various neurodegenerative diseases.

Publications

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  • Besche HC, Sha Z, Kukushkin NV, Peth A, Hock EM, Kim W, Gygi S, Gutierrez JA, Liao H, Dick L, Goldberg AL. Autoubiquitination of the 26S Proteasome on Rpn13 Regulates Breakdown of Ubiquitin Conjugates. EMBO J 2014; 33:1159-76. PubMed
  • Cohen S, Lee D, Zhai B, Gygi SP, Goldberg AL. Trim32 reduces PI3K-Akt-FoxO signaling in muscle atrophy by promoting plakoglobin-PI3K dissociation. J Cell Biol 2014; 204:747-58. PubMed
  • Piccirillo R, Demontis F, Perrimon N, Goldberg AL. Mechanisms of muscle growth and atrophy in mammals and Drosophila. Dev Dyn 2014; 243:201-15. PubMed
  • Demontis F, Piccirillo R, Goldberg AL, Perrimon N. The influence of skeletal muscle on systemic aging and lifespan. Aging Cell 2013; 12:943-9. PubMed
  • Lee D, Goldberg AL. SIRT1 protein, by blocking the activities of transcription factors FoxO1 and FoxO3, inhibits muscle atrophy and promotes muscle growth. J Biol Chem 2013; 288:30515-26. PubMed
  • Peth A, Nathan JA, Goldberg AL. The ATP costs and time required to degrade ubiquitinated proteins by the 26 S proteasome. J Biol Chem 2013; 288:29215-22. PubMed
  • Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int J Biochem Cell Biol 2013; 45:2333-47. PubMed
  • Goldberg AL. Development of proteasome inhibitors as research tools and cancer drugs. J Cell Biol 2012; 199:583-8. PubMed
  • Berko D, Tabachnick-Cherny S, Shental-Bechor D, Cascio P, Mioletti S, Levy Y, Admon A, Ziv T, Tirosh B, Goldberg AL, Navon A. The Direction of Protein Entry into the Proteasome Determines the Variety of Products and Depends on the Force Needed to Unfold Its Two Termini. Mol Cell 2012. PubMed
  • Raju RM, Goldberg AL, Rubin EJ. Bacterial proteolytic complexes as therapeutic targets. Nat Rev Drug Discov 2012; 11:777-89. PubMed
  • Cohen S, Zhai B, Gygi SP, Goldberg AL. Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy. J Cell Biol 2012; 198:575-89. PubMed
  • Nijhawan D, Zack TI, Ren Y, Strickland MR, Lamothe R, Schumacher SE, Tsherniak A, Besche HC, Rosenbluh J, Shehata S, Cowley GS, Weir BA, Goldberg AL, Mesirov JP, Root DE, Bhatia SN, Beroukhim R, Hahn WC. Cancer vulnerabilities unveiled by genomic loss. Cell 2012; 150:842-54. PubMed
  • Piccirillo R, Goldberg AL. The p97/VCP ATPase is critical in muscle atrophy and the accelerated degradation of muscle proteins. EMBO J 2012; 31:3334-50. PubMed
  • 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; 144:526-38. PubMed
  • Altun M, Besche HC, Overkleeft HS, Piccirillo R, Edelmann MJ, Kessler BM, Goldberg AL, Ulfhake B. Muscle wasting in aged, sarcopenic rats is associated with enhanced activity of the ubiquitin proteasome pathway. J Biol Chem 2010; 285:39597-608. PubMed
  • Menzies FM, Hourez R, Imarisio S, Raspe M, Sadiq O, Chandraratna D, O'Kane C, Rock KL, Reits E, Goldberg AL, Rubinsztein DC. Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy. Hum Mol Genet 2010; 19:4573-86. PubMed
  • Peth A, Uchiki T, Goldberg AL. ATP-dependent steps in the binding of ubiquitin conjugates to the 26S proteasome that commit to degradation. Mol Cell 2010; 40:671-81. PubMed
  • Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, Rosenfeld R, Chen Q, Boone T, Simonet WS, Lacey DL, Goldberg AL, Han HQ. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 2010; 142:531-43. PubMed
  • Brault JJ, Jespersen JG, Goldberg AL. Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J Biol Chem 2010; 285:19460-71. PubMed
  • Yu Y, Smith DM, Kim HM, Rodriguez V, Goldberg AL, Cheng Y. Interactions of PAN's C-termini with archaeal 20S proteasome and implications for the eukaryotic proteasome-ATPase interactions. EMBO J 2010; 29:692-702. PubMed
  • Tai HC, Besche H, Goldberg AL, Schuman EM. Characterization of the Brain 26S Proteasome and its Interacting Proteins. Front Mol Neurosci 2010. PubMed
  • Lee do H, Goldberg AL. Hsp104 is essential for the selective degradation in yeast of polyglutamine expanded ataxin-1 but not most misfolded proteins generally. Biochem Biophys Res Commun 2010; 391:1056-61. PubMed
  • Peth A, Besche HC, Goldberg AL. Ubiquitinated proteins activate the proteasome by binding to Usp14/Ubp6, which causes 20S gate opening. Mol Cell 2009; 36:794-804. PubMed
  • Besche HC, Peth A, Goldberg AL. Getting to first base in proteasome assembly. Cell 2009; 138:25-8. PubMed
  • Kim HT, Kim KP, Uchiki T, Gygi SP, Goldberg AL. S5a promotes protein degradation by blocking synthesis of nondegradable forked ubiquitin chains. EMBO J 2009; 28:1867-77. PubMed
  • Cohen S, Brault JJ, Gygi SP, Glass DJ, Valenzuela DM, Gartner C, Latres E, Goldberg AL. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J Cell Biol 2009; 185:1083-95. PubMed
  • Medicherla B, Goldberg AL. Heat shock and oxygen radicals stimulate ubiquitin-dependent degradation mainly of newly synthesized proteins. J Cell Biol 2008; 182:663-73. PubMed
  • Smith DM, Chang SC, Park S, Finley D, Cheng Y, Goldberg AL. Docking of the proteasomal ATPases' carboxyl termini in the 20S proteasome's alpha ring opens the gate for substrate entry. Mol Cell 2007; 27:731-44. PubMed
  • Rock KL, York IA, Goldberg AL. Post-proteasomal antigen processing for major histocompatibility complex class I presentation. Nat Immunol 2004; 5:670-7. PubMed
  • Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004; 117:399-412. PubMed
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