FANCL ubiquitinates β-catenin and enhances its nuclear function
| Autor: | Amy E. Hanlon Newell, Jane E. Yates, Susan B. Olson, Stefanie Kaech, Kim Hien T. Dao, Grover C. Bagby, Brian J. Druker, Curtis L. Petersen, Whitney D. Nelson, Michael D. Rotelli |
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| Rok vydání: | 2012 |
| Předmět: |
Pluripotent Stem Cells
Hematopoiesis and Stem Cells Immunology Fanconi Anemia Complementation Group L Protein Models Biological Biochemistry Cell Line Mice Ubiquitin Fanconi anemia medicine Animals Humans Cyclin D1 FANCL Progenitor cell beta Catenin Cell Nucleus Mice Knockout biology Fanconi Anemia Complementation Group C Protein Ubiquitination Wnt signaling pathway Hematopoietic stem cell Cell Biology Hematology Fetal Blood Hematopoietic Stem Cells medicine.disease Molecular biology Recombinant Proteins Ubiquitin ligase Cell biology Fanconi Anemia HEK293 Cells medicine.anatomical_structure biology.protein Stem cell TCF Transcription Factors Signal Transduction |
| Zdroj: | Blood. 120:323-334 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Bone marrow failure is a nearly universal complication of Fanconi anemia. The proteins encoded by FANC genes are involved in DNA damage responses through the formation of a multisubunit nuclear complex that facilitates the E3 ubiquitin ligase activity of FANCL. However, it is not known whether loss of E3 ubiquitin ligase activity accounts for the hematopoietic stem cell defects characteristic of Fanconi anemia. Here we provide evidence that FANCL increases the activity and expression of β-catenin, a key pluripotency factor in hematopoietic stem cells. We show that FANCL ubiquitinates β-catenin with atypical ubiquitin chain extension known to have nonproteolytic functions. Specifically, β-catenin modified with lysine-11 ubiquitin chain extension efficiently activates a lymphocyte enhancer-binding factor-T cell factor reporter. We also show that FANCL-deficient cells display diminished capacity to activate β-catenin leading to reduced transcription of Wnt-responsive targets c-Myc and Cyclin D1. Suppression of FANCL expression in normal human CD34+ stem and progenitor cells results in fewer β-catenin active cells and inhibits expansion of multilineage progenitors. Together, these results suggest that diminished Wnt/β-catenin signaling may be an underlying molecular defect in FANCL-deficient hematopoietic stem cells leading to their accelerated loss. |
| Databáze: | OpenAIRE |
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