John W.B. Hershey, Ph.D., Ph.D.
Clinical Interests
Dr. Hershey’s laboratory is interested in the mechanism of initiation of protein synthesis in
eukaryotes, how the process is regulated, and how it may contribute to cancer. His laboratory has
focused on the structure/function of the mammalian initiation factors, has purified them and has
cloned their cDNAs. They also 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 Drs. Chris Fraser and James Evans
(UC Davis), high resolution structures of eIF3 and its sub-complexes are being determined by Xray 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, eIF3f by CDK11p46 upon entry into apoptosis (in collaboration with Dr. Jiaqi
Shi, University of Arizona), and eIF3h by showing that phosphorylation is required for malignant
properties when overexpressed, 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 are being 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 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.
Title
Specialty
Department
Division
Professor Emeritus
Biological Chemistry, Cancer
Biological Chemistry and Molecular Medicine
Biological Chemistry
John W.B. Hershey, Ph.D., Ph.D.
Center/Program Affiliation
Select Recent Publications
UC Davis Comprehensive Cancer Center
Fraser, C.S., J.W. Hershey and J.A. Doudna The pathway of hepatitis C virus mRNA recruitment to
the human ribosome. Nat. Struct. Mol. Biol. 2009. 16, 397-404.
Ludwig, A.L., C. Raske, F. Tassone, D. Garcia-Arocena, J.W. Hershey and P.J. Hagerman
Translation of the FMR1 mRNA is not influenced by AGG interruptions. Nucl. Acids Res. 2009.
37, 6896-6904.
Shi,J, J.W. Hershey and M.A. Nelson Phosphorylation of the eukarhyotic initiation factor 3f by
cyclin dependent protein kinase 11 during apoptosis. FEBS Lett. 2009. 583: 971-977.
Fraser, S.C., K.E. Berry, J.W.B. Hershey and J.A. Doudna eIF3j is located in the decoding center of
the human 40S ribosomal subunit. Molec. Cell 2008. 26, 811-819.
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 Structural Characterization of the Human Eukaryotic Initiation Factor 3
Protein Complex by Mass Spectrometry. Mol. Cell. Proteomics 2008. 6: 1135-1146.
Zhang, L., Z. Smit-McBride, X. Pan, J. Rheinhardt and J.W.B.. Hershey An Oncogenic Role for the
Human Translation Initiation Factor eIF3h. J. Biol. Chem. 2008. 283: 24047-24060.
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 Mass spectrometry reveals
modularity and a complete subunit interaction map of the eukaryotic translation factor eIF3. Proc.
Natl. Acad. Sci. 2008. USA 105: 18139-18144.
Zhang, L., X. Pan and J.W.B. Hershey Individual Overexpression of Five Subunits of Human
Translation Initiation Factor eIF3 Promotes Malignant Transformation of Immortal Fibroblast Cells.
J. Biol. Chem. 2007. 282: 5790-5800.
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