TCF-4 isoforms absent in TCF-4 mutated MSI-H colorectal cancer cells colocalize with nuclear CtBP and repress TCF-4-mediated transcription.
TCF-4 is the main effector of the Wnt/Wingless signalling pathway. As with other TCF/LEF factors, numerous alternative splicings at its 3' end affect its expression. Such a mechanism leads to the synthesis of numerous TCF-4 isoforms among which some contain binding domains for CtBP, an ubiquitous transcriptional corepressor. Of interest, we described a frequent TCF-4 frameshift mutation in mismatch-repair deficient colorectal cancers (MSI-H cancers) that leads to the selective loss of TCF-4 isoforms with CtBP binding abilities. We provide here data that argue for a partial colocalization of CtBP with TCF-4 isoforms containing CtBP binding domains in cellulo, and for a functional role of CtBP in repressing TCF-4 mediated transcription. We also demonstrate that such a colocalization is not observed in MSI-H colorectal cancer cells that harbour the TCF-4 frameshift mutation, and that CtBP is not able to repress TCF-4-mediated transcription in this context. Taken together, our results strongly suggest that CtBP would play a role in regulating TCF-4 mediated transcription upon its binding with some TCF-4 isoforms encoded by alternatively spliced mRNA. They also suggest a role for TCF-4 frameshift mutation during MSI-H colorectal tumour progression, by regulating the relative proportion of the different TCF-4 isoforms.
Inserm, U762, Paris, F-75010, France.
P
P
Cuilliere-Dartigues
J
J
El-Bchiri
A
A
Krimi
O
O
Buhard
P
P
Fontanges
J-F
JF
Fléjou
R
R
Hamelin
A
A
Duval
D000429:Alcohol Oxidoreductases / Q000378:metabolism* / Q000502:physiology; D017398:Alternative Splicing / Q000502:physiology; D020137:Base Pair Mismatch; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D016368:Frameshift Mutation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D058118:Transcription Factor 7-Like 2 Protein; D014158:Transcription, Genetic / Q000502:physiology*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein