Probing the Functions of KLF2 Downregulation

Project: Research project

Project Details

Description

KLF2 is a member of the Kruppel-like family of transcription factors, which control diverse processes in many different cell types. KLF2 has documented functions in a wide variety of cells and tissues, including lung development, vascular mural cell migration, adipocyte development, and erythropoiesis. Within the immune system, KLF2 also subserves multiple functions, including regulation of T and B cell traffic, maintenance of myeloid cell quiescence, and anti-inflammatory actions in endothelial cells. More recently, KLF2 has been implicated in regulation of T helper differentiation, but mechanisms underlying this function are not yet clear. KLF2 is somewhat unique among lymphocyte transcription factors in that its expression is rapidly lost upon activation through Ag receptors (TCR and BCR), and this loss of expression is at both the mRNA and protein levels. A similar process occurs in both myeloid cells and in endothelium, where conditional inactivation of KLF2 leads to an activated, pro-inflammatory state. Whether downregulation of KLF2 is an essential aspect of the development or function of other cell types, including lung, blood vessels, adipocytes, and early erythrocytes, is unknown. Downregulation of KLF2 following Ag receptor engagement occurs rapidly at both the transcriptional and post-translational levels, generally within ~8-12 hours. Mechanisms which mediate transcriptional silencing have not been identified. In contrast, it is well established that KLF2 downregulation at the protein level is via the well studied ubiquitin-proteosome system, and several E3 ubiquitin ligases which mediate this effect in various non-hematopoietic cells have been identified. Further, the key lysine residue essential for ubiquitination has been identified, and mutation of this lysine to arginine completely blocks proteolytic destruction of KLF2. However, none of these studies have addressed the basic question of why this occurs, and no biological functions in any cell types have been identified which require KLF2 downregulation. We will address this issue by producting a novel mouse strain in which KLF2 expression can be enforced in any cell type which expresses the cre recombinase (Aim 1), and use this mouse to understand the functions of KLF2 downregulation in the T cell compartment (Aim 2). Further, the mutant mice which we produce will be ideal for approaching this question in numerous other cell types as well. As KLF2 downregulation is a feature of many, if not most or all cell types in which it is expressed, this project will make a major impact inthe field.
StatusFinished
Effective start/end date4/1/163/31/20

Funding

  • National Institute of Allergy and Infectious Diseases (1R21AI119137-01A1)

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