Randal Kaufman, Ph.D.

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 (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. 

Randal Kaufman's Bio

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.
 

Education

  • Postdoctoral, Center for Cancer Research, M.I.T.
  • Ph.D., Stanford University
  • B.A., University of Colorado
     

Other appointments

  • 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

Differentiation of neural stem cells

Publications

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

Show All Select Publications

The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4.

Pathak SS, Liu D, Li T, de Zavalia N, Zhu L, Li J, Karthikeyan R, Alain T, Liu AC, Storch KF, Kaufman RJ, Jin VX, Amir S, Sonenberg N, Cao R

Neuron 2019 Aug 26 ;

Publisher Correction: Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics.

Carreras-Sureda A, Jaña F, Urra H, Durand S, Mortenson DE, Sagredo A, Bustos G, Hazari Y, Ramos-Fernández E, Sassano ML, Pihán P, van Vliet AR, González-Quiroz M, Torres AK, Tapia-Rojas C, Kerkhofs M, Vicente R, Kaufman RJ, Inestrosa NC, Gonzalez-Billault C, Wiseman RL, Agostinis P, Bultynck G, Court FA, Kroemer G, Cárdenas JC, Hetz C

Nat Cell Biol 2019 Jul ;21(7):913

Proinsulin misfolding is an early event in the progression to type 2 diabetes.

Arunagiri A, Haataja L, Pottekat A, Pamenan F, Kim S, Zeltser LM, Paton AW, Paton JC, Tsai B, Itkin-Ansari P, Kaufman RJ, Liu M, Arvan P

Elife 2019 Jun 11 ;8

Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics.

Carreras-Sureda A, Jaña F, Urra H, Durand S, Mortenson DE, Sagredo A, Bustos G, Hazari Y, Ramos-Fernández E, Sassano ML, Pihán P, van Vliet AR, González-Quiroz M, Torres AK, Tapia-Rojas C, Kerkhofs M, Vicente R, Kaufman RJ, Inestrosa NC, Gonzalez-Billault C, Wiseman RL, Agostinis P, Bultynck G, Court FA, Kroemer G, Cárdenas JC, Hetz C

Nat Cell Biol 2019 Jun ;21(6):755-767

Targeting the unfolded protein response in head and neck and oral cavity cancers.

Cole DW, Svider PF, Shenouda KG, Lee PB, Yoo NG, McLeod TM, Mutchnick SA, Yoo GH, Kaufman RJ, Callaghan MU, Fribley AM

Exp Cell Res 2019 Sep 1 ;382(1):111386

Disulfiram (Antabuse) Activates ROS-Dependent ER Stress and Apoptosis in Oral Cavity Squamous Cell Carcinoma.

Shah O'Brien P, Xi Y, Miller JR, Brownell AL, Zeng Q, Yoo GH, Garshott DM, O'Brien MB, Galinato AE, Cai P, Narula N, Callaghan MU, Kaufman RJ, Fribley AM

J Clin Med 2019 May 6 ;8(5)

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