Peter B. Bitterman, M.D. Professor Department of Medicine Yale University, 1976, M.D. bitte001@umn.edu 612-624-0999 - office 612-625-7615 - lab

Research Interests:

Translational Control of Cell Fate

Our research program seeks to understand how the activity state of the protein synthesis apparatus regulates the life and death of a cell. We have discovered that over expression of translation initiation factor eIF4E selectively suppresses apoptosis in cancer cells and fibroblasts from fibrotic lesions, whereas inhibition of eIF4E function activates apoptosis in these cells without harming normal cells. Research opportunities exist for graduate studies to address 3 major questions:

1. What are the specific steps in the process of translation initiation that are integral to apoptosis regulation? Experiments to answer this question utilize genetic modulation of the translation initiation apparatus to pinpoint critical amino acid residues required for apoptosis regulation.

2. Which specific mRNA species encoding rescue or death proteins are subject to translational control? This line of investigation features novel microarray screening procedures we have developed to discover and characterize those mRNAs responsible for rescue from apoptosis.

3. Can we therapeutically target the protein synthesis apparatus with small organic molecules or gene constructs designed to promote apoptosis in cancer cells or fibroblasts? Our laboratory is developing new high throughput techniques to test novel translational repressors as potential anticancer and antifibrotic agents in collaboration with Medicinal Chemists in the College of Pharmacy.

Our investigations feature a dynamic collaborative network of biochemists, cancer biologists, lung biologists and medicinal chemists. Graduate students will interact with a diverse group of trainees as part of our NIH sponsored training grant. Graduate students will join a cohort spanning an educational continuum beginning with honors undergraduates satisfying their research requirement, M.D. and M.D.-Ph.D. students, through post-doctoral fellows.

Selected Publications:

• O Larsson, DM Perlman, D Fan, CS Reilly, M Peterson, C Dahlgren, Z Liang, S Li, VA Polunovsky, C Wahlestedt and PB Bitterman. 2006. Apoptosis resistance downstream of eIF4E: Post transcriptional activation of an antiapoptotic transcript carrying a consensus hairpin structure. Nucleic Acids Research. (in Press).

• Jacobson BA, Alter MD, Kratzke MG, Frizelle SP, Zhang Y, Peterson MS, Avdulov S, Mohorn RP, Whitson BA, Bitterman PB, Polunovsky VA, Kratzke RA.  2006. Repression of cap-dependent translation attenuates the transformed phenotype in non-small cell lung cancer both in vitro and in vivo. Cancer Res. Apr 15; 66 (8):4256-62.

• Ghosh P, Park C, Peterson MS, Bitterman PB, Polunovsky VA, Wagner CR. 2005. Synthesis and evaluation of potential inhibitors of eIF4E cap binding to 7-methyl GTP. Bioorg Med Chem Lett. Apr 15;15(8):2177-80.

• Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman DM, Manivel JC, Sonenberg N, Yee D, Bitterman PB, Polunovsky VA.  2004. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell Jun; 5 (6):553-63.

• Li S, Perlman DM, Peterson MS, Burrichter D, Avdulov S, Polunovsky VA, Bitterman PB. 2004. Translation initiation factor 4E blocks endoplasmic reticulum-mediated apoptosis. J Biol Chem. May 14; 279(20):21312-7.

• Li S, Takasu T, Perlman DM, Peterson MS, Burrichter D, Avdulov S, Bitterman PB, Polunovsky VA. 2003. Translation factor eIF4E rescues cells fromMyc-dependent apoptosis by inhibiting cytochrome c release.J Biol Chem. 278:3015-22.

• Li S, Sonenberg N, Gingras AC, Peterson M, Avdulov S, Polunovsky VA, Bitterman PB. 2002. Translational control of cell fate: availability of phosphorylation sites on translational repressor 4E-BP1 governs its proapoptotic potency. Mol Cell Biol. 22:2853-61.
  
  

Last updated: August 10, 2006