We have developed potent dominant negatives (DNs), termed A-ZIPs, that abolish the DNA binding of B-ZIP transcription factors in a leucine zipper-dependent manner. These DNs (including those that interact with CREB, CEBP, AP1, ATF2 and TFE) are ideal reagents for exploring the transcriptional targets of B-ZIPs involved in, among other things, chemotheraputic resistance of human cancer cells. To identify B-ZIP gene targets, we are expressing dominant negatives using E1-deleted adenovirus that infect 100% of the cells in culture. Using DNA microarray chips, we have started to identify transcriptional targets in A549 human lung cells infected with the DNs at a multiplicity of infection (MOI) of 10. Under these conditions, cisplatin sensitivity is increased threefold due to the interaction of A-FOS. We have additional data on three pairs of samples: E1-deleted virus versus uninfected cells; A-CEBP–infected cells versus empty virus-infected cells; and A-CREB–infected cells versus empty virus-infected cells. We used two probes: Cy5 labelled dominant negative-infected cells, and Cy3 labelled empty adenoviral-infected cells. Differences in hybridization intensity of the two probes to the microarray reveal the activity of the dominant negatives. We used a microarray chip containing 1,342 genes on a polylysine-coated glass slide. Empty virus infection after one day caused 1.5% of the genes to be misregulated, of which approximately half were overexpressed. A-CEBP or A-CREB, when compared with empty virus infection, changed the expression patterns of about 3% of the genes at least threefold with 25% of these genes being upregulated. We plan on presenting data showing changes in gene expression resulting from addition of cisplatin. Identifying A-ZIP alterations of gene expression of cisplatin-treated cells will suggest potential transcriptional targets of the B-ZIP family in cancer-resistant cells.