Open AccessWnt signaling inside the nucleus
Author(s) -
Shitashige Miki,
Hirohashi Setsuo,
Yamada Tesshi
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2007.00716.x
Subject(s) - wnt signaling pathway , adenomatous polyposis coli , transactivation , cancer research , colorectal cancer , biology , carcinogenesis , enhancer , transcription factor , creb , catenin , microbiology and biotechnology , beta catenin , signal transduction , cancer , genetics , gene
Accumulation of the β‐catenin protein and transactivation of a certain set of T‐cell factor (TCF)‐4 target genes by accumulated β‐catenin have been considered crucial in colorectal carcinogenesis. In the present review, we summarize nuclear proteins that interact with, and regulate, the β‐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 β‐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 β‐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 β‐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. ( Cancer Sci 2008; 99: 631–637)