Figure 1. Negative feedback regulation of inflammatory responses. The transcription factor NF-êB activates transcription of its target genes, such as A20 and IêBá. Products of these genes function as negative regulators of NF-êB and limit the duration of its activation. This is desirable because persistent activation of NF-êB can lead to various pathogenic conditions such as chronic inflammation, autoimmune diseases, and cancer.
Figure 2. The role of DSIF in the control of inflammatory responses. Upon NF-êB activation, DSIF is recruited to the A20 and IêBá genes and contributes to the negative feedback regulation in a unique manner. DSIF facilitates the expression of these genes by stimulating capping, splicing, and export of their mRNAs. Otherwise, these steps are rate-limiting, and A20 and IêBá proteins are not synthesized successfully.
Activity of NF-êB is usually transient because products of these genes function as negative regulators of NF-êB, resulting in a negative feedback and limiting the duration of NF-êB activation (Figure 1). In certain diseases NF-êB activation becomes persistent, perhaps due to an interruption of this feedback loop.
NF-êB activation results in recruitment of the protein DSIF at the target genes A20 and IêBá. The researchers confirmed the role of DSIF in the negative feedback regulation of NF-êB activity by downregulating a protein subunit of DSIF and comparing the treated cells with controls. In untreated cells the levels of proteins for the target genes A20 and IêBá are high. Although the levels diminish significantly in 30 minutes following a process called TNF-á induction, which is caused by degradation of the proteins, within 2 hours the levels recover. In knockdown cells, however, the levels remained diminished 2 hours after TNF-á induction.
Further investigations using chromatin immunoprecipitation assays revealed abnormalities in the synthesis of A20 and IêBá proteins in the knock down cells. A significant portion of the A20 and IêBá mRNAs in the knockdown cells were uncapped and unspliced (Fig. 2).
The researchers also studied how export was affected in DSIF knockdown cells. Export of mature mRNAs from the nucleus to the cytoplasm is a highly regulated process incorporating quality assurance checks. The researchers prepared RNA from cytosolic and nuclear cell fractions for comparison. In knockdown cells following TNF-á induction, the nuclear fractions had much larger amounts of A20 and IêBá than the cytosolic fractions, suggesting accumulation in the nucleus.
The impact observed on the synthesis and export of A20 and IêBá in DSIF knockdown cells was striking. A20 and IêBá are also responsible for regulating other cell signalling processes and it is likely that the effects on associated signalling processes contribute to the overall impact of DSIF knockdown.
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