The integrin cytoplasmic domain has been shown to modulate several cellular functions, including cell proliferation, adhesion, migration, and intracellular signaling. The beta(1) integrin subunits beta(1C) and beta(1A), which contain variant cytoplasmic domains, differentially affect cancer and normal cell functions. To identify target genes selectively regulated by these beta(1) cytoplasmic variants, stable cell transfectants expressing either beta(1A) or beta(1C) under the control of a doxycycline-inducible promoter were obtained using murine beta(1)-deficient GD25 cells. Screening of 1176 murine cDNAs using first-strand cDNA of mRNA isolated from either beta(1C)- or beta(1A)-expressing cells showed a striking differential expression of few genes. The differential expression of two genes, MCP-3 and BRCA2 (monocyte chemoattractant protein-3 and breast cancer susceptibility gene 2, respectively), whose products are involved, respectively, in chemotaxis and embryonic proliferation, was confirmed by Northern blot analysis. Increased MCP-3 and decreased BRCA2 mRNA levels in cells expressing beta(1C) compared to those in cells expressing beta(1A) were observed. Since beta(1C) and beta(1A) stable cell transfectants showed comparable adhesion to fibronectin, upregulation of MCP-3 and downregulation of BRCA2 mRNA levels did not appear to be due to a differential ability of the beta(1C) cells to adhere to the beta(1) ligand fibronectin. Overall, our data show that beta(1) integrin cytoplasmic domain variants control expression of downstream target genes in a differential manner without affecting cell adhesion.