Peter Bitterman, MD

Professor of Medicin
Vice Chair for Research, Department of Medicine
Associate Director, MD/PhD Program, Medical School
bitte001@umn.edu

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.


Selected  Recent Publications 

Vlasova IA, Tahoe NM, Fan D, Larsson O, Rattenbacher B, Sternjohn JR, Vasdewani J, Karypis G, Reilly CS, Bitterman PB, Bohjanen PR. Conserved GU-rich elements mediate mRNA decay by binding to CUG-binding protein 1. Molecular Cell 2008; 29(2):263-70. 

Xia H, Diebold D, Nho RS, Perman D, Kahm J, Kleidon J, Avdulor A, Peterson M, Bitterman PB, Henke CA. Pathological integrin signaling enhances proliferation of primary lung fibroblasts  from patients' idiopathic pulmonary fibrosis. 2008,  J Exp Medicine 2008; 205(7):1659-72.

Ghosh P, Cheng J, Chou TF, Jia Y, Avdulov S, Bitterman PB, Polunovsky VA, Wagner CR.  Expression, purification and characterization of recombinant mouse translation initiation factor eIF4E as a dihydrofolate reductase (DHFR) fusion protein. Protein Expr Purif. 2008; 60(2):132-9.

Larsson O, Diebold D, Fan D, Peterson M, Nho R, Bitterman PB, Henke CA.  Fibrotic myofibroblasts manifest genome-wide derangements of translational control.  PLoS ONE.  2008; 3(9):e3220.

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.

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.

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. 

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.

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

Completed Research Support:

1R01 HL073719 Bitterman (PI) 09/01/03—6/30/07
NIH/NHLBI

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