Wnt signaling inside the nucleus.
Accumulation of the beta-catenin protein and transactivation of a certain set of T-cell factor (TCF)-4 target genes by accumulated beta-catenin have been considered crucial in colorectal carcinogenesis. In the present review, we summarize nuclear proteins that interact with, and regulate, the beta-catenin and TCF and lymphoid enhancer factor (LEF) transcriptional complexes. Our recent series of proteomic studies has also revealed that various classes of nuclear proteins participate in the beta-catenin-TCF-4 complex and modulate its transcriptional activity. Furthermore, the protein composition of the TCF-4-containing nuclear complex is not fixed, but is regulated dynamically by endogenous programs associated with intestinal epithelial cell differentiation and exogenous stimuli. Restoration of the loss-of-function mutation of the adenomatous polyposis coli (APC) gene in colorectal cancer cells does not seem to be a realistic approach with currently available medical technologies, and only signaling molecules downstream of the APC gene product can be considered as targets of pharmacological intervention. Nuclear proteins associated with the beta-catenin-TCF-4 complex may include feasible targets for molecular therapy against colorectal cancer. Recently, an inhibitor of the interaction between CREB-binding protein and beta-catenin was shown to efficiently shut down the transcriptional activity of TCF-4 and induce apoptosis of colorectal cancer cells. We also summarize current strategies in the development of drugs against Wnt signaling.
Shitashige
Miki
M
Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuoh-ku, Tokyo 104-0045, Japan.
Hirohashi
Setsuo
S
Yamada
Tesshi
T
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000494:pharmacology / Q000627:therapeutic use; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin