The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression.
Fanconi anemia (FA) is an inherited bone marrow failure syndrome associated with a progressive decline in hematopoietic stem cells, developmental defects, and predisposition to cancer. These various phenotypic features imply a role of FA proteins in molecular events regulating cellular homeostasis. Interestingly, we previously found that the Fanconi C protein (FANCC) interacts with the C-terminal-binding protein-1 (CtBP1) involved in transcriptional regulation. Here we report that FANCC with CtBP1 forms a complex with β-catenin, and that β-catenin activation through glycogen synthase kinase 3β inhibition leads to FANCC nuclear accumulation and FA pathway activation, as measured by the Fanconi D2 protein (FANCD2) monoubiquitination. β-catenin and FANCC nuclear entry is defective in FA mutant cells and in cells depleted of the Fanconi A protein or FANCD2, suggesting that integrity of the FA pathway is required for FANCC nuclear activity. We also report that FANCC with CtBP1 acts as a negative regulator of Dickkopf-1 (DKK1) expression, and that a FA disease-causing mutation in FANCC abrogates this function. Our findings reveal that a defective FA pathway leads to up-regulation of DKK1, a molecule involved in hematopoietic malignancies.
Centre Hospitalier Université Laval Research Center, Québec, QC, Canada G1V 4G2 and Departments of Psychiatry and Neurosciences and Pediatrics, Université Laval, Québec, QC, Canada G1V 0A6.
Caroline C
CC
Huard
Cédric S
CS
Tremblay
Audrey
A
Magron
Georges
G
Lévesque
Madeleine
M
Carreau
D004789:Enzyme Activation; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism*; D052218:Fanconi Anemia Complementation Group C Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D014158:Transcription, Genetic
C501126:DKK1 protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D036341:Intercellular Signaling Peptides and Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3