Gfi1 ubiquitination and proteasomal degradation is inhibited by the ubiquitin ligase Triad1
- 1 November 2007
- journal article
- Published by American Society of Hematology
- Vol. 110 (9), 3128-3135
- https://doi.org/10.1182/blood-2006-11-058602
Abstract
Growth factor independence 1 (Gfi1) is a transcriptional repressor essential for the function and development of many different hematopoietic lineages. The Gfi1 protein expression is regulated by the ubiquitin-proteasome system. In granulocytes, Gfi1 is rapidly degraded by the proteasome, while it is more stable in monocytes. How the ubiquitination and degradation of Gfi1 is regulated is unclear. Here, we show that the ubiquitin ligase Triad1 interacts with the DNA-binding domain of Gfi1. Unexpectedly, we found that Triad1 inhibited Gfi1 ubiquitination, resulting in a prolonged half-life. Down-regulation of endogenous Triad1 by siRNAs resulted in increased Gfi1 ubiquitination. In U937 cells, Triad1 caused an increase in endogenous Gfi1 protein levels and slowed cell proliferation in a similar manner when Gfi1 itself was expressed. A Triad1 mutant that lacks the Gfi1-binding domain did not affect Gfi1 levels and proliferation. Because neither proteasome-ubiquitin nor Triad1 ubiquitin ligase activity was required for the inhibition of Gfi1 ubiquitination, these data suggest that Triad1 competes for Gfi1 binding with as yet to be identified E3 ubiquitin ligases that do mark Gfi1 for proteasomal degradation. The finetuning of Gfi1 protein levels regulated by Triad1 defines an unexpected role for this protein in hematopoiesis.Keywords
This publication has 42 references indexed in Scilit:
- Transcriptional Repressor Gfi1 Integrates Cytokine-Receptor Signals Controlling B-Cell DifferentiationPLOS ONE, 2007
- The Transcriptional Repressor Gfi1 Controls STAT3-Dependent Dendritic Cell Development and FunctionImmunity, 2005
- Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cellsNature, 2004
- Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cellsThe EMBO Journal, 2004
- Evidence implicating Gfi-1 and Pim-1 in pre-T-cell differentiation steps associated with β-selectionThe EMBO Journal, 1998
- Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein ɛ-deficient miceProceedings of the National Academy of Sciences of the United States of America, 1997
- Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein α-deficient miceProceedings of the National Academy of Sciences of the United States of America, 1997
- Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities.The EMBO Journal, 1996
- Requirement of Transcription Factor PU.1 in the Development of Multiple Hematopoietic LineagesScience, 1994
- Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein.Molecular and Cellular Biology, 1993