CELL SIGNALING PATHWAYS ELICITED BY ASBESTOS

In recent years, it has become apparent that minerals can trigger alte rations in gene expression by initiating signaling events upstream of gene transactivation. These cascades may be initiated at the cell surf ace after interaction of minerals with the plasma membrane either thro ugh receptorlike mechanisms or integrins. Alternatively signaling path ways may be stimulated by active oxygen species generated both during phagocytosis of minerals and by redox reactions on the mineral surface . At least two signaling cascades linked to activation of transcriptio n factors, i.e., DNA-binding proteins involved in modulating gene expr ession and DNA replication, are stimulated after exposure of lung cell s to asbestos fibers in vitro. These include nuclear factor kappa B (N F kappa B) and the mitogen-activated protein kinase (MAPK) cascade imp ortant in regulation of the transcription factor, activator protein-1 (AP-1). Both NF kappa B and AP-1 bind to specific DNA sequences within the regulatory or promoter regions of genes that are critical to cell proliferation and inflammation. Unraveling the cell signaling cascade s initialed by mineral dusts and pharmacologic inhibition of these eve nts may be important for the control and treatment of mineral-associat ed occupational diseases.