The DNA binding architectural protein, TCF, and the transcriptional activator, beta-catenin, form a complex that regulates the expression of diverse target genes during early development and carcinogenesis. As an approach to modulating transcription by this complex, we selected an RNA aptamer that binds to the DNA binding domain of TCF-1. The aptamer interfered with the binding of TCF-1 to its specific DNA recognition sequences in vitro and also inhibited DNA binding of cellular TCF-1. We also developed the truncated version of the aptamer for efficient delivery to the cells. Structural analysis of the truncated aptamer revealed that a stem-loop with an internal loop was responsible for the binding to TCF-1. Similar approach may well be applicable to other proteins, especially DNA binding transcription factors, in order to modulate their DNA binding and transcriptional activity in the cells. (c) 2005 Elsevier Inc. All rights reserved.