The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Caroline C Huard, Cedric Tremblay, Audrey Magron, Georges Levesque, Madeleine Carreau

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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-terminalbinding protein-1 (CtBP1) involved in transcriptional regulation. Here we report that FANCC with CtBP1 forms a complex with ?-catenin, and that ?-catenin activation through glycogen synthase kinase 3? inhibition leads to FANCC nuclear accumulation and FA pathway activation, as measured by the Fanconi D2 protein (FANCD2) monoubiquitination. ?-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.
Original languageEnglish
Pages (from-to)2152 - 2157
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume111
Issue number6
DOIs
Publication statusPublished - 2014

Cite this

Huard, Caroline C ; Tremblay, Cedric ; Magron, Audrey ; Levesque, Georges ; Carreau, Madeleine. / The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression. In: Proceedings of the National Academy of Sciences. 2014 ; Vol. 111, No. 6. pp. 2152 - 2157.
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abstract = "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-terminalbinding protein-1 (CtBP1) involved in transcriptional regulation. Here we report that FANCC with CtBP1 forms a complex with ?-catenin, and that ?-catenin activation through glycogen synthase kinase 3? inhibition leads to FANCC nuclear accumulation and FA pathway activation, as measured by the Fanconi D2 protein (FANCD2) monoubiquitination. ?-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.",
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The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression. / Huard, Caroline C; Tremblay, Cedric; Magron, Audrey; Levesque, Georges; Carreau, Madeleine.

In: Proceedings of the National Academy of Sciences, Vol. 111, No. 6, 2014, p. 2152 - 2157.

Research output: Contribution to journalArticleResearchpeer-review

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