The histidine triad protein Hint1 interacts with Pontin and Reptin and inhibits TCF-beta-catenin-mediated transcription.
Pontin and Reptin previously were identified as nuclear beta-catenin interaction partners that antagonistically modulate beta-catenin transcriptional activity. In this study, Hint1/PKCI, a member of the evolutionary conserved family of histidine triad proteins, was characterised as a new interaction partner of Pontin and Reptin. Pull-down assays and co-immunoprecipitation experiments show that ... Hint1/PKCI directly binds to Pontin and Reptin. The Hint1/PKCI-binding site was mapped to amino acids 214-295 and 218-289 in Pontin and Reptin, respectively. Conversely, Pontin and Reptin bind to the N-terminus of Hint1/PKCI. Moreover, by its interaction with Pontin and Reptin, Hint1/PKCI is associated with the LEF-1/TCF-beta-catenin transcription complex. In this context, Hint1/PKCI acts as a negative regulator of TCF-beta-catenin transcriptional activity in Wnt-transfected cells and in SW480 colon carcinoma cells as shown in reporter gene assays. Consistent with these observations, Hint1/PKCI represses expression of the endogenous target genes cyclin D1 and axin2 whereas knockdown of Hint1/PKCI by RNA interference increases their expression. Disruption of the Pontin/Reptin complex appears to mediate this modulatory effect of Hint1/PKCI on TCF-beta-catenin-mediated transcription. These data now provide a molecular mechanism to explain the tumor suppressor function of Hint1/PKCI recently suggested from the analysis of Hint1/PKCI knockout mice.
Mesh Terms:
Amino Acid Sequence, Animals, Blotting, Western, Cell Line, Tumor, Cyclin D1, DNA Helicases, HeLa Cells, Humans, Mice, Molecular Sequence Data, NIH 3T3 Cells, Nerve Tissue Proteins, TCF Transcription Factors, Trans-Activators, Transcription Factors, Transcriptional Activation, Transfection, beta Catenin
Amino Acid Sequence, Animals, Blotting, Western, Cell Line, Tumor, Cyclin D1, DNA Helicases, HeLa Cells, Humans, Mice, Molecular Sequence Data, NIH 3T3 Cells, Nerve Tissue Proteins, TCF Transcription Factors, Trans-Activators, Transcription Factors, Transcriptional Activation, Transfection, beta Catenin
J. Cell. Sci.
Date: Jul. 15, 2005
PubMed ID: 16014379
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