Chemical- and radiation-induced carcinogenesis is a multistage process involving tumor initiation, promotion and progression. Dr. Huberman hypothesizes that tumor-promoter-induced differentiation of tissue monocytes results in an improper expansion of macrophage pools, causing tissue damage and inflammation and thereby contributing to the required clonal expansion of initiated cells during tumor promotion. He is investigating tumor-promoter-induced macrophage differentiation of myeloid precursors and the signal-transduction system that leads to this differentiation. His experiments will utilize the differential display technique to identify genes differentially expressed in human myeloid HL-60 leukemia cell variants that are either susceptible or resistant to macrophage differentiation. A functional role for the identified genes will be established by examining the effect of antisense-mediated inhibition of the cognate mRNA in HL-60 cells, as well as by over expressing sense cDNA in appropriate resistant cell variants. Using this approach, Dr. Huberman has already isolated a gene coding for a novel kinase, which is induced by the tumor promoter phorbol 12-myristate 13-acetate (PMA) in HL-60 cells, absent in resistant cells, and critical for PMA-mediated HL-60 differentiation. Dr. Huberman proposes experiments designed to determine the precise role of this kinase in the signal transduction pathway leading to macrophage differentiation. He proposes to establish the kinase's relationships to other mediators of differentiation, characterize the biological function of this kinase, and investigate the kinase's targets and effectors using both gene-expression and protein contact strategies. In addition, Dr. Huberman proposes experiments aimed at isolating and characterizing additional mediators of macrophage differentiation using an expression screen and genetic complementation approach.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemical Pathology Study Section (CPA)
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Poland, Alan P
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University of Chicago
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Floryk, Daniel; Huberman, Eliezer (2006) Mycophenolic acid-induced replication arrest, differentiation markers and cell death of androgen-independent prostate cancer cells DU145. Cancer Lett 231:20-9
Glesne, D; Huberman, E (2006) Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation. Oncogene 25:4086-98
Glesne, David; Vogt, Stefan; Maser, Jorg et al. (2006) Regulatory properties and cellular redistribution of zinc during macrophage differentiation of human leukemia cells. J Struct Biol 155:2-11
Zheng, Xi; Ryan, Amanda; Patel, Namrata et al. (2005) Synergistic stimulatory effect of 12-O-tetradecanoylphorbol-13-acetate and capsaicin on macrophage differentiation in HL-60 and HL-525 human myeloid leukemia cells. Int J Oncol 26:441-8
Cohen, Shenhav; Dovrat, Sara; Sarid, Ronit et al. (2005) JAK-STAT signaling involved in phorbol 12-myristate 13-acetate- and dimethyl sulfoxide-induced 2'-5' oligoadenylate synthetase expression in human HL-60 leukemia cells. Leuk Res 29:923-31
Floryk, Daniel; Huberman, Eliezer (2005) Differentiation of androgen-independent prostate cancer PC-3 cells is associated with increased nuclear factor-kappaB activity. Cancer Res 65:11588-96
Hansson, Annette; Marin, Yari E; Suh, Junghan et al. (2005) Enhancement of TPA-induced growth inhibition and apoptosis in myeloid leukemia cells by BAY 11-7082, an NF-kappaB inhibitor. Int J Oncol 27:941-8
Floryk, Daniel; Tollaksen, Sandra L; Giometti, Carol S et al. (2004) Differentiation of human prostate cancer PC-3 cells induced by inhibitors of inosine 5'-monophosphate dehydrogenase. Cancer Res 64:9049-56
Gavin, Igor M; Glesne, David; Zhao, Yong et al. (2004) Spermine acts as a negative regulator of macrophage differentiation in human myeloid leukemia cells. Cancer Res 64:7432-8
Baccam, Mekhine; Huberman, Eliezer (2003) Bacterial IMPDH gene used for the selection of mammalian cell transfectants. Biotechniques 34:1220-2, 1224, 1226 passim

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