Jeffrey M. Arbeit, M.D.

The goal of my laboratory is to determine the molecular control of epithelial carcinogenesis and its modulation by genetic and epigenetic mechanisms. Currently, we are focusing on alteration of prostate carcinogenesis by hypoxic signaling (low oxygen tension), nutrient availability or altered cellular redox potential. Specifically, we are testing the role of three molecules, HIF-1α, mTOR and ref-1, in regulation of prostate and epithelial carcinogenesis. HIF-1α (hypoxia-inducible factor-1alpha) is a primary regulator of hypoxic signaling (Arbeit 2002). HIF-1α is a “master regulatory transcription factor” that activates the transcription of genes controlling a variety of cellular functions important for malignant progression including angiogenesis, glucose transport and metabolism, cellular proliferation, and tissue invasion (Arbeit 2002). Mammalian target of rapamycin (mTOR) is a large molecule (290 kD) that can function as a sensor of cellular nutrient and energy status (Dennis et al. 2001; Fang et al. 2001; Kimball 2001; Patel et al. 2002). mTOR activates global protein synthesis by increasing ribosome biogenesis, and regulates mRNA translation, particularly of molecules with long 5’UTR’s. Molecules whose mRNA’s contain such 5’UTR’s of complex secondary structure include, VEGF, c-myc and ornithine decarboxlyase (ODC), each of which regulate angiogenesis and neoplastic and malignant cellular proliferation. A recent report also demonstrates cross-talk between mTOR and HIF-1 α signaling pathways (Hudson et al. 2002). Redox-exchange factor (ref-1) catalyzes reduction of oxidized transcription factors, which restores their function. Target ref-1 transcription factors are involved in proliferation and genome stability. Ref-1 also targets HIF-1 α for reduction and reactivation.

To test how these environmental conditions affect carcinogenic progression, we have created novel transgenic and knockout mice wherein key components of the hypoxic or nutritional-sensing pathways are overexpressed or lacking in function in either skin or prostatic epithelium. After defining the biology and molecular perturbations induced by these discrete genetic changes in prostate epithelium alone, we will tackle the more complex question of how alterations in these pathways will affect carcinogenic progression in well-characterized transgenic or knockout models of prostate neoplasia or cancer development. These models can also serve as platforms to test efficacy of novel antineoplastic agents in prostate cancer.

Web Site Descriptor References:

Arbeit JM. Quiescent hypervascularity mediated by gain of HIF-1 alpha function. Cold Spring Harbor Symposia on Quantitative Biology. 2002;67:133-142.

Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G. Mammalian TOR: a homeostatic ATP sensor. Science. 2001;294(5544):1102-1105.

Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science. 2001;294(5548):1942-1945.

Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Molecular and Cellular Biology. 2002;22(20):7004-7014.

Kimball SR. Regulation of translation initiation by amino acids in eukaryotic cells. Progress in Molecular and Subcellular Biology. 2001;26:155-184.

Patel J, McLeod LE, Vries RG, Flynn A, Wang X, Proud CG. Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors. European Journal of Biochemistry. 2002;269(12):3076-3085.

Recent Arbeit Lab Publications:

Elson DA, Riley RR, Lacy A, Thordarson G, Talamantes FJ, Arbeit JM. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis. Cancer Research. 2000;60:1267-1275.

Ryan HE, Poloni M, McNulty W, Elson DA, Gassmann M, Arbeit JM, Johnson RS. Hypoxia-inducible factor-1 α is a positive factor in solid tumor growth. Cancer Research. 2000;60:4010-4016.

Elson DA, Ryan HE, Snow JW, Johnson RS, Arbeit JM. Coordinate upregulation of HIF-1 α and HIF-1 target genes during multistage epidermal carcinogenesis and wound healing. Cancer Research. 2000;60:6189-6195.

Elson DA, Thurston G, Huang LE, Ginzinger DG, McDonald DM, Johnson RS, Arbeit JM. Induction of hypervascularity without leak or inflammation in transgenic mice overexpressing hypoxia-inducible factor-α. Genes and Development. 2001;15:2520-2532.

Komuves LG, Michael E, Arbeit JM, Ma XK, Kwong A, Stelnicki E, Rozenfeld S, Morimune M, Yu QC, Largman C. HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation. Developmental Dynamics. 2002;224(1):58-68.

Arbeit JM. Quiescent hypervascularity mediated by gain of HIF-1 alpha function. Cold Spring Harbor Symposia on Quantitative Biology. 2002;67:133-142.

Arbeit JM. Mouse models of cervical cancer. Comparative Medicine. 2003;53(3):256-258.

Li G, Gustafson-Brown C, Hanks SK, Nason K, Arbeit JM, Pogliano K, Wisdom RM, Johnson RS. c-Jun is essential for organization of the epidermal leading edge. Developmental Cell. 2003;4(6):865-877.

Riley RR, Brake T, Duensing S, Lambert PM, Munger K, Arbeit J. Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Research. (in press)

Dr. Jeffrey M. Arbeit's CV