TY - JOUR
T1 - DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes
AU - Diamant, Gil
AU - Amir-Zilberstein, Liat
AU - Yamaguchi, Yuki
AU - Handa, Hiroshi
AU - Dikstein, Rivka
N1 - Israel Science Foundation; Israel Cancer Research Fund; Israel Ministry of Science and Technology for Japan-Israel Scientific Research Cooperation [9999]; Pearl Welinsky Merlo Foundation Scientific Research Progress FundWe would like to thank Dr. Sandra Moshonov for critical reading and editing of the manuscript and Dr. Aaron Shatkin for anti-HCE antibodies. This work was supported by grants from the Israel Science Foundation, Israel Cancer Research Fund, Israel Ministry of Science and Technology for Japan-Israel Scientific Research Cooperation (#9999), and The Pearl Welinsky Merlo Foundation Scientific Research Progress Fund. R.D. is the incumbent of the Ruth and Leonard Simon Chair of Cancer Research.
PY - 2012/10/25
Y1 - 2012/10/25
N2 - 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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=84868152650&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.celrep.2012.08.041
DO - https://doi.org/10.1016/j.celrep.2012.08.041
M3 - مقالة
SN - 2211-1247
VL - 2
SP - 722
EP - 731
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -