John Hershey, Ph.D.

Professor Emeritus

4408 Tupper Hall
Ph: (530) 752-3235
Cell: (510) 701-2315  
jwhershey@ucdavis.edu

• • The laboratory group is interested in the mechanism of initiation of protein synthesis in eukaryotes, how the process is regulated, and how it may contribute to cancer.  We focus on the structure/function of the mammalian initiation factors, have purified them and have cloned their cDNAs.  Currently, we are studying the structure of eIF3, the largest of the factors, which contains at least 13 non-identical subunits.  eIF3 sub-complexes are generated by expressing recombinant proteins in baculovirus-infected insect cells and the functions of the individual subunits are characterized biochemically.  In collaboration with Dr. Jennifer Doudna (UC Berkeley), high resolution structures of eIF3 and its sub-complexes are being determined by X-ray crystallography and cryo-electron microscopy.
  
  • A second major effort concerns phosphorylation as a means to regulate initiation factor activities and protein synthesis.  Having characterized the phosphorylation of eIF4B by RSK1 following serum stimulation, and eIF3f by CDK11p46 (in collaboration with Dr. Mark Nelson, University of Arizona) upon entry into apoptosis, we are focusing on other eIF3 subunits that are phosphorylated.  Phosphorylation sites have been identified by mass spectrometry (in collaboration with Julie Leary, UC Davis) and mutated to Ala and Glu to study the effects on eIF3 activity.
  
  • A third project concerns the role of translation in cell malignancy.  Recent studies involving the overexpression of each of 12 eIF3 subunits in NIH3T3 cells identified five subunits that cause the malignant transformation of this immortal cell line.  The mechanism of malignant transformation by eIF3 subunit overexpression and the effects of RNAi knockdown of their expression are being pursued.
  
  • A fourth project, in collaboration with Prof. Paul Hagerman (UC Davis), involves elucidation of how
  the fragile-X protein, FMRP, is translated from its mRNA.  The occurrence of CGG-repeat elements in the 5’-UTR of the mRNA is expected to inhibit initiation, yet FMRP protein is detected in patients with CGG-repeat expansions.  We are studying the mechanism of initiation on this mRNA and how the expected deleterious effects of the CGG-repeat elements are bypassed.

• Dr. Pankaj Alone
  Dr. Masaaki Sokabe
  Teresa Yokoi

1. LeFebvre, A.K., N.L. Korneeva, M. Trutschl, U. Cvek, R.D. Duzan, C.A. Bradley, J.W.B. Hershey †, and R.E. Rhoads (2006) Translation initiation Factor eIF4G-1 Binds to eIF3 Through the eIF3e Subunit.  J. Biol. Chem. 281, 22917-22932.

2. Timchenko, L.T., E. Salisbury, G.L. Wang, H.D. Nguyen, J.H. Albrecht, J.W. Hershey and N.A. Timchenko (2006) Age-specific CUGBP1-eIF2 complex increases translation of C/EBP beta in old liver.  J. Biol. Chem. 281, 32806-32819.

3. Zhang, L., X. Pan and J.W.B. Hershey (2007) Individual Overexpression of Five Subunits of Human Translation Initiation Factor eIF3 Promotes Malignant Transformation of Immortal Fibroblast Cells. J. Biol. Chem. 282, 5790-5800.

4. Komarova, A.V., E. Real, A.M. Borman, M. Brocard, P. England, N. Tordo, J.W.B. Hershey, K.M. Kean and Y. Jacob (2007) Rabies Virus Matrix Protein Interplay with eIF3, New Insights into Rabies Virus Pathogenesis.  Nucl. Acids Res. 35, 1522-1532.

5. Damoc, E., C.S. Fraser, M. Zhou, H. Videler, G.L. Mayeur, J.W.B. Hershey, J.A. Doudna, C.V. Robinson and J.A. Leary (2007) Structural Characterization of the Human Eukaryotic Initiation Factor 3 Protein Complex by Mass Spectrometry.  Mol. Cell. Proteomics 6, 1135-1146.

6. Fraser, S.C., K.E. Berry, J.W.B. Hershey and J.A. Doudna (2007) eIF3j is located in the decoding center of the human 40S ribosomal subunit.  Molec. Cell 26, 811-819.

7. Cano, V.S.P., G.A. Jeon, H.E. Johansson, C.A. Henderson, J-H. Park, S.R. Valentini, J.W.B. Hershey and M.H. Park (2008) Mutational analyses of human eIF5A-1 – Identification of amino acid residues critical for eIF5A activity and hypusine modification.  FEBS J. 275, 44-58.

8. Isken, Olaf , Yoon Ki Kim, Nao Hosoda, Greg L. Mayeur, John W.B. Hershey and Lynne E. Maquat (2008) Upf1 Phosphorylation Triggers Translational Repression During Nonsense-Mediated mRNA Decay.  Cell 133, 314-327.

9. Zhang, L., Z. Smit-McBride, X. Pan, J. Rheinhardt and J.W.B.. Hershey (2008) An Oncogenic Role for the Human Translation Initiation Factor eIF3h.  J. Biol. Chem., in press.

10. Zhou, M., A.M. Sandercock, C.S. Fraser, G. Ridlova, E. Sstephens, M.R. Schenauer, T. Yokoi-Fong, D. Baarsky, J.A. Leary, J.W.B. Hershey, J. Doudna and C.V. Robinson (2008) Mass spectrometry reveals modularity and a complete subunit interaction map of the eukaryotic translation factor eIF3.  Proc. Natl. Acad. Sci. USA, in press.