John Hershey, Ph.D.

Emeritus Professor

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 initation 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 12 non-identical subunits.  eIF3 sub-complexes are generated by expressing recombinant proteins in baculovirus-infected insect cells and the fnctions 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 reghulate 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 will be identified by mass spectrometry 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 the 12 eIF3 subunits in NIH3T3 cells identified five subunits 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, involves elucidation of how the fragile-X protein, FMRP, is translated from its mRNA.  The occurence 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.

• LiLi Zhang
• Greg Mayeur
• Purvi Patel 

1. Timchenko LT, Salisbury E, Wang GL, Nguyen H, Albrecht JH, Hershey JW, Timchenko NA.
   Age-specific CUGBP1-eIF2 complex increases translation of CCAAT/enhancer-binding protein beta in old liver.
   J Biol Chem. 2006 Oct 27 ;281(43):32806-19. Epub 2006 Aug 24.
   
2. LeFebvre AK, Korneeva NL, Trutschl M, Cvek U, Duzan RD, Bradley CA, Hershey JW, Rhoads RE.
   Translation initiation factor eIF4G-1 binds to eIF3 through the eIF3e subunit.
   J Biol Chem. 2006 Aug 11 ;281(32):22917-32. Epub 2006 Jun 9.
   
3. Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Taunton J, Hershey JW, Blenis J, Pende M, Sonenberg N.
   The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity.
   EMBO J. 2006 Jun 21 ;25(12):2781-91. Epub 2006 Jun 8.
   
4. Shi J, Kahle A, Hershey JW, Honchak BM, Warneke JA, Leong SP, Nelson MA.
   Decreased expression of eukaryotic initiation factor 3f deregulates translation and apoptosis in tumor cells.
   Oncogene. 2006 Aug 10 ;25(35):4923-36. Epub 2006 Mar 13.
   
5. Fraser CS, Hershey JW.
   Movement in ribosome translocation.
   J Biol. 2005 ;4(2):8. Epub 2005 Jun 27.
   
6. Miyamoto S, Patel P, Hershey JW.
   Changes in ribosomal binding activity of eIF3 correlate with increased translation rates during activation of T lymphocytes.
   J Biol Chem. 2005 Aug 5 ;280(31):28251-64. Epub 2005 Jun 9.
   
7. Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW.
   Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases.
   EMBO J. 2004 Apr 21 ;23(8):1761-9. Epub 2004 Apr 8.
   
8. Fraser CS, Lee JY, Mayeur GL, Bushell M, Doudna JA, Hershey JW.
   The j-subunit of human translation initiation factor eIF3 is required for the stable binding of eIF3 and its subcomplexes to 40 S ribosomal subunits in vitro.
   J Biol Chem. 2004 Mar 5 ;279(10):8946-56. Epub 2003 Dec 19.
   
9. Clement PM, Henderson CA, Jenkins ZA, Smit-McBride Z, Wolff EC, Hershey JW, Park MH, Johansson HE.
   Identification and characterization of eukaryotic initiation factor 5A-2.
   Eur J Biochem. 2003 Nov ;270(21):4254-63.
   
10. Mayeur GL, Fraser CS, Peiretti F, Block KL, Hershey JW.
    Characterization of eIF3k: a newly discovered subunit of mammalian translation initiation factor elF3.
    Eur J Biochem. 2003 Oct ;270(20):4133-9.