The basic leucine zipper transcription factor E4bp4 is essential for various immunological processes, most notably the development of natural killer (NK) cells. E4bp4 is required at the point of lineage commitment when NK cell progenitors develop from common lymphoid progenitors. E4bp4 promotes NK cell development by directly regulating the expression of other transcription factors, including Eomes and Id2. Despite its critical role, little is known about how the functions of the E4bp4 protein are regulated within the cellular environment. This study demonstrates that E4bp4 is post translationally modified by phosphorylation and SUMOylation and that these modifications directly regulate the protein's function. In the absence of either modification, E4bp4 is both a more potent transcriptional activator and transcriptional repressor. In NK cells, the absence of post translational modifications on E4bp4 promotes the expression of target genes Notch1 and E2A. Most strikingly, when expressed in hematopoietic progenitor cells, versions of E4bp4 lacking phosphorylation or SUMOylation sites, promote the development of up to three times more NK cells than the wild type form of E4bp4. This work has implications for the production of NK cells for use in immunotherapy and provides the first evidence that SUMOylation of an individual transcription factor protein can regulate a highly complex cellular process.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:659511 |
| Date | January 2014 |
| Creators | Kostrzewski, Tomasz |
| Contributors | Brady, Hugh |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/25527 |
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