Abstract
Fbxo7 is a key player in the differentiation and function of numerous blood cell types, and in neurons, oligodendrocytes and spermatocytes. In an effort to gain insight into the physiological and pathological settings where Fbxo7 is likely to play a key role, we sought to define the transcription factors which direct FBXO7 expression. Using sequence alignments across 28 species, we defined the human FBXO7 promoter and found that it contains two conserved regions enriched for multiple transcription factor binding sites. Many of these have roles in either neuronal or haematopoietic development. Using various FBXO7 promoter reporters, we found ELF4, Pax5 and c-Myb have functional binding sites that activate transcription. We find endogenous Pax5 is bound to the FBXO7 promoter in pre-B cells, and that the exogenous expression of Pax5 represses Fbxo7 transcription in early pro-B cells.
Highlights
F-box proteins (FBP) are exchangeable subunits within Skp1Cullin1-F-box protein (SCF)-type E3 ubiquitin ligases
One island in the distal promoter region was 125bp in length (À1275 to À1150), while the other in the proximal promoter region was 400bp in length and overlapped the Transcription start sites (TSS) and start of exon 1 (À300 to þ100). These islands contained the majority of transcription factor (TF) binding sites, and selected regions from 13 of the species surveyed are shown in Fig. 1A. 32 putative binding sites were identified for 24 different TFs (17 in the distal region; 15 in the proximal region)
A similar proximal promoter was reported in the pig, it was limited to 1000 bp upstream of the TSS [35]
Summary
F-box proteins (FBP) are exchangeable subunits within Skp1Cullin1-F-box protein (SCF)-type E3 ubiquitin ligases. These enzymes conjugate a 76aa ubiquitin peptide onto proteins, and this post-translational modification can precipitate that target’s degradation, change of localisation or activity. Fbxo functions outside of canonical ubiquitin-dependent pathways, for example, acting as scaffolds for other regulatory proteins [1]. Fbxo affects many processes including, the cell cycle, enhancing cyclin D/ Cdk activity by acting as a scaffold for their assembly and stabilising the cyclin-dependent kinase inhibitor, p27 [6]; the regulation of stress-induced mitophagy via the PINK1/Parkin pathway [7]; NF-
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