DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes
NF-κB is central for immune response and cell survival, and its deregulation is linked to chronic inflammation and cancer through poorly defined mechanisms. IκBα and A20 are NF-κB target genes and negative feedback regulators. Upon their activation by NF-κB, DSIF is recruited, P-TEFb is released, an...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2012-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124712002823 |
| _version_ | 1828358899888029696 |
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| author | Gil Diamant Liat Amir-Zilberstein Yuki Yamaguchi Hiroshi Handa Rivka Dikstein |
| author_facet | Gil Diamant Liat Amir-Zilberstein Yuki Yamaguchi Hiroshi Handa Rivka Dikstein |
| author_sort | Gil Diamant |
| collection | DOAJ |
| description | NF-κB is central for immune response and cell survival, and its deregulation is linked to chronic inflammation and cancer through poorly defined mechanisms. IκBα and A20 are NF-κB target genes and negative feedback regulators. Upon their activation by NF-κB, DSIF is recruited, P-TEFb is released, and their elongating polymerase II (Pol II) C-terminal domain (CTD) remains hypophosphorylated. We show that upon DSIF knockdown, mRNA levels of a subset of NF-κB targets are not diminished; yet much less IκBα and A20 protein are synthesized, and NF-κB activation is abnormally prolonged. Further analysis of IκBα and A20 mRNA revealed that a significant portion is uncapped, unspliced, and retained in the nucleus. Interestingly, the Spt5 C-terminal repeat (CTR) domain involved in elongation stimulation through P-TEFb is dispensable for IκBα and A20 regulation. These findings assign a function for DSIF in cotranscriptional mRNA processing when elongating Pol II is hypophosphorylated and define DSIF as part of the negative feedback regulation of NF-κB. |
| first_indexed | 2024-04-14T03:34:06Z |
| format | Article |
| id | doaj.art-b8c130f9389b4f7dace87ccd253ca933 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-14T03:34:06Z |
| publishDate | 2012-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-b8c130f9389b4f7dace87ccd253ca9332022-12-22T02:14:50ZengElsevierCell Reports2211-12472012-10-012472273110.1016/j.celrep.2012.08.041DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback GenesGil Diamant0Liat Amir-Zilberstein1Yuki Yamaguchi2Hiroshi Handa3Rivka Dikstein4Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Information, Tokyo Institute of Technology, Yokohama 226-8501, JapanDepartment of Biological Information, Tokyo Institute of Technology, Yokohama 226-8501, JapanDepartment of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, IsraelNF-κB is central for immune response and cell survival, and its deregulation is linked to chronic inflammation and cancer through poorly defined mechanisms. IκBα and A20 are NF-κB target genes and negative feedback regulators. Upon their activation by NF-κB, DSIF is recruited, P-TEFb is released, and their elongating polymerase II (Pol II) C-terminal domain (CTD) remains hypophosphorylated. We show that upon DSIF knockdown, mRNA levels of a subset of NF-κB targets are not diminished; yet much less IκBα and A20 protein are synthesized, and NF-κB activation is abnormally prolonged. Further analysis of IκBα and A20 mRNA revealed that a significant portion is uncapped, unspliced, and retained in the nucleus. Interestingly, the Spt5 C-terminal repeat (CTR) domain involved in elongation stimulation through P-TEFb is dispensable for IκBα and A20 regulation. These findings assign a function for DSIF in cotranscriptional mRNA processing when elongating Pol II is hypophosphorylated and define DSIF as part of the negative feedback regulation of NF-κB.http://www.sciencedirect.com/science/article/pii/S2211124712002823 |
| spellingShingle | Gil Diamant Liat Amir-Zilberstein Yuki Yamaguchi Hiroshi Handa Rivka Dikstein DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes Cell Reports |
| title | DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes |
| title_full | DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes |
| title_fullStr | DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes |
| title_full_unstemmed | DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes |
| title_short | DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes |
| title_sort | dsif restricts nf κb signaling by coordinating elongation with mrna processing of negative feedback genes |
| url | http://www.sciencedirect.com/science/article/pii/S2211124712002823 |
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