Peter B. Bitterman, M.D.
Department of Medicine
Yale University, 1976, M.D.
612-624-0999 - office
612-625-7615 - lab
Translational Control of Cell Fate
Our research program seeks to understand how the activity state of the protein synthesis apparatus regulates cell function. We have discovered that pathological activation of the translation initiation complex, eIF4F, imparts primary fibroblasts and epithelial cells with autonomy for growth and survival and is on the causal pathway to cancer. In contrast, inhibition of eIF4F function restores physiological control of these functions. Our research program addresses 3 major questions:
1. What steps in the process of translation initiation are integral to the regulation of proliferation and survival? Experiments to answer this question utilize genetic and pharmacological modulation of the translation initiation apparatus to link chemical structure to physiological function.
2. Which specific mRNA species encoding master regulatory proteins are subject to translational control? This line of investigation features novel microarray and informatics procedures we have developed. Our goal is to begin deciphering the encrypted rules governing the translational control step in the flow of genetic information.
3. Can we therapeutically target the protein synthesis apparatus with small molecules designed to eliminate autonomy of cancer cells or fibroblasts in fibrotic lesions? Our laboratory has developed novel 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, bioengineers, 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, MD and MD/PhD students, through post-doctoral fellows
- Kim Y, Von Weyman L, Larsson O, Fan D, Underwood J, Hecht S, Polunovsky VA, Bitterman PB. The eukaryotic initiation factor 4E binding protein family of translational repressors: Sentinels at a translational control checkpoint in lung tumor defense. Cancer Res. (accepted).
- Fan D, Bitterman PB and Larsson O. 2009. Regulatory Element Identification in Subsets of Transcripts: Comparison and Integration of Current Computational Methods. RNA 15(8):1469-82.
- Ghosh B, Benyumov AO, Ghosh P, Jia Y, Avdulov S, Dahlberg PS, Peterson M, Smith K, Polunovsky VA, Bitterman PB, Wagner CR. 2009. Nontoxic chemical interdiction of the epithelial-to-mesenchymal transition by targeting cap-dependent translation. ACS Chem Biol. May 15; 4(5):367-77.
- Larsson O, D Diebold, D Fan, M Peterson, RS Nho, Bitterman PB and C A Henke. 2008. Fibrotic Myofibroblasts Manifest Genome-Wide Derangements of Translational Control. PLoS One, 16; 3(9), e3220.
- Xia H, D Diebold, R Nho, D Perlman, J Kleidon, J Kahm, S Avdulov, M Peterson, J Nerva, Bitterman PB, Henke C. 2008. Pathological Integrin Signaling Enhances Proliferation of Primary Lung Fibroblasts from Patients with Idiopathic Pulmonary Fibrosis. J. Exp. Med., 205(7): 1659-72.
- Vlasova I.A., Tahoe N.M., Fan D., Larsson O., Vasdewani J., Karypis G., Bitterman PB, Bohjanen PR. 2008. Conserved GU-rich elements mediate mRNA decay by binding to CUG-binding protein 1. Mol Cell.; 29(2): 263-70.
- Larsson O, S Li, OA Issaenko, S Avdulov, M Peterson, K Smith, Bitterman PB and VA Polunovsky. 2007. eIF4E-induced progression of primary HMECs along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. Cancer Res., 67 (14): 1-11.
- Larsson O, Perlman DM, Fan D, Reilly CS, Peterson M, Dahlgren C, Liang Z, Li S, Polunovsky VA, Wahlestedt C, Bitterman PB. 2006. Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an anti-apoptotic transcript carrying a consensus hairpin structure. Nucleic Acids Res.34(16):4375-86.
- 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, 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.
- 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 PB, 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.
- Polunovsky VA, Rosenwald IB, Tan A, White J, Chiang L, Sonenberg N, Bitterman PB. Translational control of programmed cell death: eukaryotic translation initiation factor 4E blocks apoptosis in growth-factor-restricted fibroblasts with physiologically regulated or deregulated. Myc. Mol Cell Biol 1996; 16:6573-6581.