Preface: Transcription Factor as Molecular Targets: Is Transcription Factor Decoy a Novel Drug ? [Hot topic: Transcription Factor as Molecular Targets (Guest Editor: Ryuichi Morishita)]

Correct regulation of gene expression is essential both to normal development and to the correct functioning of the adult organism. Such regulation is usually achieved at the level of DNA transcription, a process that controls which genes are transcribed into RNA by the enzyme RNA polymerase, although post-transcriptional regulation is also important. The transcription of specific genes is controlled by regulatory proteins known as transcription factors. Transcription factors have been grouped in families on the basis of shared DNA-binding motifs. Other regions of the factors interact with RNA polymerase and its associated proteins to increase or decrease the rate of transcription. The vital role of these factors, together with the fact that a single factor can affect the expression of many genes, suggests that the inactivation of a transcription factor as a result of an inherited mutation is incompatible with survival. Therefore, numerous pharmacological drugs including steroids have been identified to affect the transcription factors. However, only few drugs have been developed initially to target the transcriptional regulation, since transcription factors work within nuclei. From early 1990, several researchers including us tried to modulate the transcription factors using molecular strategy. Initially, overexpression of TAR-containing sequences (TAR decoys) in a double copy murine retroviral vector was used to render cells resistant to HIV replication [1]. Currently, TAR decoys, short RNA oligonucleotides corresponding to the HIV TAR sequence, are used to inhibit HIV expression and replication by blocking the binding of the HIV regulatory protein Tat to the authentic TAR region. However, such RNA decoys are very difficult to use in vivo. In addition, the regulation of decoy expression is also problematic. To overcome these issues, synthetic ds DNA with high affinity for transcription factors has been developed as a “decoy” cis-element to bind the transcription factors and block the activation of genes mediating such diseases, resulting in an effective therapy for treating diseases, since transfection of ds ODN corresponding to the cis sequence will result in attenuation of the removal of the transfactors from the endogenous cis-element with subsequent modulation of gene expression [2]. This approach is particularly attractive for several reasons: 1) the potential drug targets (transcription factors) are plentiful and readily identifiable, 2) the synthesis of the sequence-specific decoy is relatively simple and can be targeted to specific tissues, 3) knowledge of the exact molecular structure of the target transcription factor is unnecessary, and 4) decoy ODN may be more effective than antisense ODN in blocking constitutively expressed factors as well as multiple transcription factors that bind to the same cis element. Although the mechanisms of actions of antisense ODN are still unclear, the principle of the transcription factor decoy approach is simply the reduction of promoter activity due to the inhibition of binding of a transcription factor to a specific sequence in the promoter region [ (Fig. 1). In 1996, clinical application of “decoy” against E2F was approved by FDA to treat neointimal “For figure please see the pdf file.” TF = transcription factor, decoy = decoy ODN, antisense = antisense ODN, siRNA = small interfering RNA.] hyperplasia in vein bypass grafts which results in failure in up to 50 % of grafts within a period of 10 years [3]. The present targets for decoy ODN are wide-spread from cell cycle regulatory transcription factors such as E2F to inflammatory regulatory transcription factors such as NFkB. Although there are still many unresolved issues in the clinical application of decoy strategy, its utility could be widespread as a useful tool for gene therapy in other diseases. Recent progress in the backborne of DNA in decoy including ab-anomeric, methylphosphonate- and phosphorothioate oligonucleotides have also given the opportunity to treat various diseases. In addition, circular dumbbell (ribbon) double-stranded ODN may also become a potent tool to develop decoy strategy. In this exciting hot topic issue, transcription factor decoy ODN have been discussed as the potential drugs to treat various diseases. REFERENCES [1] Bielinska. A., Shivdasani, R.A., Zhang, L., Nabel, G.J. (1990) Science 250, 997-1000. [2] Morishita, R., Higaki, J., Tomita, N., Ogihara, T. (1998) Circ. Res. 82, 1023-1028. [3] Mann, M.J., Whittemore, A.D., Donaldson, M.C., Belkin, M., Conte, M.S., Polak, J.F., Orav, E.J., Ehsan, A., Dell'Acqua, G., Dzau, V.J. (1999) Lancet 354, 1493-1498.