Research Program: Tumor Biology and Progression
Professor, Department of Medicine

bitte001@umn.edu
612-624-5175 — office
612-625-7615 — lab
Preferred contact method: e-mail

Dr. Bitterman's clinical profile
(University of Minnesota Physicians Web site)

Dr. Bitterman received his M.D. from Yale University in 1976. He is a professor of Medicine and director of Pulmonary and Critical Care at the University of Minnesota Medical School. He is also the director of research at the Lillihei Heart Institute at the University of Minnesota and the associate director of the Combined MD/PhD Training Program in the Medical School.

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 confers normal cells with autonomy and is required for breast and lung cancer cell tumorigenicity. Our research seeks to answer 3 major questions:

• What are the specific steps in the process of translation initiation that are integral to the acquisition of autonomy? Experiments to answer this question utilize genetic modulation of the translation initiation apparatus to pinpoint critical amino acid residues required for this activity.
• Which specific mRNA species encoding proteins conferring autonomy are subject to translational control? This line of investigation features novel microarray screening procedures we have developed to discover and characterize the responsible mRNAs.
• Can we therapeutically target the protein synthesis apparatus with small organic molecules or gene constructs designed to incapacitate cancer cells?

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 and post doctoral fellows will interact with a diverse group of trainees as part of our NIH sponsored training grant; joining 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

Larsson O, Li S, Issaenko OA, Avdulov S, Peterson M, Smith K, Bitterman PB, Polunovsky VA. Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. Cancer Res. 2007;67:6814-24.

Polunovsky VA, Bitterman PB. The cap-dependent translation apparatus integrates and amplifies cancer pathways. RNA Biol. 2006;3:10-7.

Larsson O, Perlman DM, Fan D, Reilly CS, Peterson M, Dahlgren C, Liang Z, Li S, Polunovsky VA, Wahlestedt C, Bitterman PB. Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an anti-apoptotic transcript carrying a consensus hairpin structure. Nucleic Acids Res. 2006;34:4375-86.

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

Ghosh P, Park C, Peterson MS, Bitterman PB, Polunovsky VA, Wagner CR. Synthesis and evaluation of potential inhibitors of elF4E cap binding to 7-methyl GTP. Bioorg Med Chem Lett. 2005:15:2177-80.

Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman DM, Manivel JC, Sonenberg N, Yee D, Bitterman PB, Polunovsky VA. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell, 2004; 5:553-563.

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

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

Li S, Sonenberg N, Gingras A-C, Peterson M, Avdulov S, Polunovsky VA, Bitterman PB. Translational Control of Cell Fate: Availability of Phosphorylation sites on Translational Repressor 4E-BP1 Governs its proapoptotic potency. Mol Cell Biol. 2002;22:2853-2861.

Polunovsky VA, Gingras A-G, Sonenberg N, Peterson M, Tan A, Rubins JB, Manivel JC, Bitterman PB. Translational control of the antiapoptotic function of Ras. J Biol Chem. 2000;275:24776-24780.

Tan A, Bitterman P, Sonenberg N, Peterson M, Polunovsky V. Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1. Oncogene 2000;19:1437-1447.