TUMOR PROMOTER MACROPHAGE DIFFERENTIATION AND APOPTOSIS

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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.