Professor of Medicine Vice Chair for Research, Department of Medicine Associate Director, MD/PhD Program, Medical School Contact Information
Research Interests: 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 translation initiation complex eIF4F imparts primary fibroblasts and epithelial cells with autonomy for growth and survival and is required for cancer cells to maintain a malignant phenotype. In contrast, inhibition of eIF4F function activates apoptosis in these cells without harming normal cells. Our research program addresses 3 major questions:
What steps in the process of translation initiation are integral to the regulation of proliferation and apoptosis? Experiments to answer this question utilize genetic modulation of the translation initiation apparatus to pinpoint critical amino acid residues required for apoptosis regulation.
Which specific mRNA species encoding master regulatory proteins are subject to translational control? This line of investigation features novel microarray and informatic procedures we have developed. Our goal is to begin deciphering the encrypted rules governing the translational control step in the flow of genetic information.
Can we therapeutically target the protein synthesis apparatus with small organic 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, 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.
Liu X, Togo S, Al-Mugotir M, Kim H, Fang Q, Kobayashi T, Wang X, Mao L, Bitterman P, Rennard S. NF-kappaB mediates the survival of human bronchial epithelial cells exposed to cigarette smoke extract. Respir Res.2008; 9:66. PMCID: PMC2567966
Ghosh B, Benyumov AO, Ghosh P, Jia Y, Avdulov S, Dahlberg PS, Peterson M, Smith K, Polunovsky VA, Bitterman PB, Wagner CR. Nontoxic chemical interdiction of the epithelial-to-mesenchymal transition by targeting cap-dependent translation. ACS Chem Biol.2009; 4(5)367-77. PMCID: PMC2796976
Fan D, Bitterman PB, Larsson O. Regulatory element identification in subsets of transcripts: comparison and integration of current computational methods. RNA. 2009;15(8):1469-82. PMCID: PMC2714745
Jacobson BA, De A, Kratzke MN, Patel MR, Jay-Dixon J, Whitson BA, Sadiq AA, Bitterman PB, Polunovsky VA, Kratzke RA. Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma. Br J Cancer. 2009 Aug 4:101(3):424-31. Epub 2009 July 14. PMCID: PMC2720234.
Kim YY, Von Weymarn L, Larsson O, Fan D, Underwood JM, Peterson MS, Hecht SS, Polunovsky VA, Bitterman PB. Eukaryotic initiation factor 4E-binding protein family of proteins: sentinels at a translational control checkpoint in lung tumor defense. Cancer Res. 2009;69(21):8455-62. PMCID: PMC2805259
Jia Y, Chiu TL, Amin EA, Polunovsky V, Bitterman PB, Wagner CR. Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP. Eur J Med Chem. 2010 Apr;45(4):1304-13 . Epub 2009 Dec6
Togo S, Sugiura H, Nelson A, Kobayashi T, Wang X, Kamio K, Kawasaki S, Bitterman P, Rennard SI, Liu Hepatic growth factor (HGF) inhibits cigarette smoke extract induced apoptosis in human bronchial epithelial cells. Exp Cell Res. 2010 Dec 10;316(20):3501-11. Epub 2010 Sep 17.PMID: 20850432
Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MA, Nan Z, Forster C, Low WC, Schoser B, Somia NV, Clark HB, Schmechel S, Bitterman PB, Gourdon G, Swanson MS, Moseley M, Ranum LP. Non-ATC-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011; 108(1):260-5. Epub 2010 Dec 20 PMCID: PMC3017129
Research Support:
1 R21 RR024398 Bitterman (PI) 12/17/07-12/16/10 NIH/NIGMS “Translational State Assay for Human Samples”
The goal of this grant is to develop an assay that is suitable for a high throughput format to quantify the translational state of human tissues.
1R01 HL076779 Bitterman (PI) 04/01/04-03/31/08 (NCE through 12/31/08) NIH/NHLBI “Antifibrotic Drug Discovery in Acute Lung Injury”
The purpose of this grant is to synthesize and evaluate hydantoin-based compounds hitting the 7-methyl guanosine mRNA cap-binding pocket of eukaryotic translation initiation factor 4E (eIF4E) that trigger fibroblast apoptosis; and to implement a novel gene expression microarray-based molecular target discovery system to primary cultures of lung fibroblasts from patients with acute lung injury to identify apoptotic regulatory proteins that are candidate molecular targets for antifibrotic drug discovery.
1 R01 CA111338 5/01/05-4/30/10 NIH/NCI “Translational Control of Breast Cancer”, Polunovsky (PI)
This study aims to test hypothesis that aberrant activation of the translation initiation apparatus is required for genesis and maintenance of breast cancer. Role: Co-Investigator
The purpose of this grant is to use an established combinatorial approach to synthesize and evaluate compounds hitting the 7-methyl guanosine mRNA cap-binding pocket of eukaryotic translation initiation factor 4E (eIF4E), a bona fide molecular target controlling the translation of mRNA encoding key regulators of fibroblast apoptosis; and to explore potential molecular targets for antifibrotic drug discovery along apoptotic pathways regulated by the extracellular matrix (ECM).
1 RO1 HL67794 Henke (PI) 4/01/02 – 03/31/07 NIH “Fibroblast Ablation as Treatment for Pulmonary Fibrosis”
The purpose of this project is (1) to generate HSV-TK/GFP expressing transgenic mice; (2) to characterize HSV-TK/GFP transgenic mice; (3) to examine the effects of GCV administration on the develpoment of pulmonary fibrosis in HSV-TK transgenic mice exposed to bleomycin. Role: Co-Investigator
PO1 AI50162 Hertz (Program PI) 9/30/01 – 8/31/06 NIH “Pathogenesis and Therapy of Chronic Lung Rejection” “Translational Repressors as Therapy for Obliterative Bronchiolitis”
The purpose of this project is (1) to use the known crystal structure of eIF4E to develop, validate and transfer gene constructs in vitro that lead to loss of translation initiation factor 4E (eIF4E) function; and test their ability to chemosensitize fibroblasts to HMG-CoA reductase inhibitor-induced apoptosis; (2) systemically test whether transfer of genes encoding those translational repressors found to be proapoptotic in Aim 1 will collaborate with HMG-CoA reductase inhibitors to diminish airway lumenal narrowing in a well established murine allograft model of airway fibroproliferation. Role: PI (Project 4)
5UO1 CA091220 Polunovsky, (PI) 06/14/01 - 05/31/05 NIH “Translational Apparatus as a Target for Cancer Drug Discovery”
The purpose of this project is (1) to synthesize a library of nucleotides predicted to inhibit binding of eIF4E to the 5’ mRNA cap; (2) to test candidate compounds in an ordered series of high and medium throughput in vitro assay systems; (3) to utilize preclinical models of breast and lung cancer to test the most promising compound (based on Aim 2 results) for its ability to collaborate with well-tolerated doses of available cancer therapeutics to inhibit xenograft growth in athymic mice. Role: Co-Investigator
