Randal Kaufman, Ph.D.[La Jolla]
I am looking forward to the opportunities for collaboration that Sanford-Burnham affords. This promises to be a very productive environment for my area of research.
Dr. Kaufman’s current research is focused on understanding the fundamental mechanisms that regulate protein folding.
Dr. Kaufman conducted his postdoctoral research at the Center for Cancer Research at M.I.T.
Complementary cell-based high-throughput screens identify novel modulators of the unfolded protein response.
Fribley AM, Cruz PG, Miller JR, Callaghan MU, Cai P, Narula N, Neubig RR, Showalter HD, Larsen SD, Kirchhoff PD, Larsen MJ, Burr DA, Schultz PJ, Jacobs RR, Tamayo-Castillo G, Ron D, Sherman DH, Kaufman RJ
J Biomol Screen. 2011 Sep;16(8):825-35
iRhoms: ERADicating the messenger in growth control signaling.
Cao SS, Kaufman RJ
Dev Cell. 2011 Apr 19;20(4):414-6
The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis.
Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, Chang L, Xu W, Miao H, Leonardi R, Chen YE, Jackowski S, Kaufman RJ
EMBO J. 2011 Apr 6;30(7):1357-75
Large-scale analysis of UPR-mediated apoptosis in human cells.
Fribley AM, Miller JR, Reist TE, Callaghan MU, Kaufman RJ
Methods Enzymol. 2011;491:57-71
The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex.
Wu J, Ruas JL, Estall JL, Rasbach KA, Choi JH, Ye L, Boström P, Tyra HM, Crawford RW, Campbell KP, Rutkowski DT, Kaufman RJ, Spiegelman BM
Cell Metab. 2011 Feb 2;13(2):160-9
Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells.
Back SH, Scheuner D, Han J, Song B, Ribick M, Wang J, Gildersleeve RD, Pennathur S, Kaufman RJ
Cell Metab. 2009 Jul;10(1):13-26
UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators.
Rutkowski DT, Wu J, Back SH, Callaghan MU, Ferris SP, Iqbal J, Clark R, Miao H, Hassler JR, Fornek J, Katze MG, Hussain MM, Song B, Swathirajan J, Wang J, Yau GD, Kaufman RJ
Dev Cell. 2008 Dec;15(6):829-40
Antioxidants reduce endoplasmic reticulum stress and improve protein secretion.
Malhotra JD, Miao H, Zhang K, Wolfson A, Pennathur S, Pipe SW, Kaufman RJ
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18525-30
Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response.
Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, Back SH, Kaufman RJ
Cell. 2006 Feb 10;124(3):587-99
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The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation.
Ravindran R, Loebbermann J, Nakaya HI, Khan N, Ma H, Gama L, Machiah DK, Lawson B, Hakimpour P, Wang YC, Li S, Sharma P, Kaufman RJ, Martinez J, Pulendran B
Nature. 2016 Mar 16;
Randal Kaufman's Research Focus
The Kaufman lab is focused on understanding the fundamental mechanisms that regulate protein folding and the cellular responses to the accumulation of unfolded proteins within the endoplasmic reticulum (ER). When proteins fail to fold correctly, they don’t work properly. Certain types of misfolded proteins defy eradication by the cellular protein degradation machinery and accumulate with age, causing cellular toxicity. In many degenerative diseases, including neurological, metabolic, genetic, and inflammatory diseases, it’s thought that the accumulation of misfolded proteins leads to cellular dysfunction and death.
Dr. Kaufman’s research has focused for more than 30 years on mechanisms that regulate proper protein folding in the ER; this work contributed to the discovery of the UPR in the mid 1980s. The UPR pathways, mediated by PERK, IRE1, and ATF6, coordinate primarily an adaptive response. More recently, his research has focused on molecular mechanisms that establish the apoptotic program in response to protein misfolding in the ER, studies that have shed light on the mechanism by which cancer cells survive in a stressful environment.
Randal Kaufman's Research Report
The major portion of our research is aimed at elucidating fundamental mechanisms that regulate protein folding and the cellular responses to the accumulation of unfolded protein within the endoplasmic reticulum (ER). Research into the fundamental processes that regulate protein synthesis and folding within the ER should have impact on the understanding of genetic diseases that result from protein folding defects.
Accumulation of unfolded proteins within the ER induces an adaptive stress response known as the unfolded protein response (UPR). The UPR is transduced from the ER lumen to the nucleus by three transmembrane proteins IRE1, ATF6, and PERK. Activation of the UPR induces the production of a family of basic leucine zipper-containing transcription factors that activate transcription of genes encoding functions to reduce the protein-folding load and increase the protein folding capacity of the ER. IRE1 is a serine/threonine protein kinase and endoribonuclease that signals transcriptional activation by initiating a novel splicing reaction on the mRNA encoding the transcription factor XBP1. UPR activation promotes trafficking of ATF6 from the ER to the Golgi where it is processed to yield a cytosolic fragment that is a potent transcriptional activator. Finally, the protein kinase PERK signals translational attenuation through phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2a) on serine residue 51. This phosphorylation also induces translation of the transcription factor ATF4. We have demonstrated that PERK/eIF2a signaling is essential for glucose-regulated insulin production by pancreatic beta cells, where defects in this pathway result in beta cell dysfunction and diabetes. The findings demonstrate an unprecedented link between glucose metabolism, protein translation, and protein folding and have implication in the treatment of diabetes. Future studies directed to elucidate the molecular logic for the UPR adaptive response will provide fundamental insight into numerous pathological conditions such as viral infection, cancer, inflammation, metabolic disease and atherosclerosis, and protein folding diseases such as
Parkinson's disease and Alzheimer's disease.
About Randal Kaufman
Dr. Randal Kaufman previously served as professor of Biological Chemistry and Internal Medicine and Howard Hughes Medical Research Institute investigator at the University of Michigan Medical School. He received his Ph.D. in pharmacology from Stanford University, where he studied gene amplification as a mechanism by which cells become resistant to anticancer agents. He was a Helen Hay Whitney fellow with Nobel Laureate Dr. Phillip Sharp at the Center for Cancer Research at the Massachusetts Institute of Technology (M.I.T.), where he developed gene transfer technologies based on gene amplification and expression in mammalian cells. He did his postdoctoral work at the Center for Cancer Research at M.I.T. In the 1980s, Dr. Kaufman’s experience with gene transfer and engineering led him to become a founding scientist at Genetics Institute Inc., where he engineered mammalian cells for high-level expression of therapeutic proteins, such as clotting factors that are now used to treat individuals with hemophilia. Dr. Kaufman joined Sanford-Burnham in 2011.
Postdoctoral, Center for Cancer Research, M.I.T.
Ph.D., Stanford University
B.A., University of Colorado
7/2011 - Present Adjunct Professor, Department of Biological Chemistry, University of Michigan, Ann Arbor, MI
Honors and Recognition
2006 AAAS Fellow
2000 Distinguished Investigator Award-MI Hemophilia Society
1999 Investigator Recognition Award, International Society of Thrombosis and Haemostasis
1998 International Association Francaise Des Hemophiles Award
1993 Dr. Murray Thelin Award