TY - JOUR
T1 - NKAP Is a Transcriptional Repressor of Notch Signaling and Is Required for T Cell Development
AU - Pajerowski, Anthony G.
AU - Nguyen, Chau
AU - Aghajanian, Haig
AU - Shapiro, Michael J.
AU - Shapiro, Virginia Smith
N1 - Funding Information:
We thank W. Pear, I. Mailliard, T. Kadesch, A. Bhandoola, D. Schultz, and M. Lazar for reagents and thoughtful discussions. We thank members of the Bhandoola and Allman laboratories for flow cytometry assistance and J. Richa for ES cell injection. This work was supported by an Arthritis Foundation Investigator Award and an NIH R21 grant to V.S.S.
PY - 2009/5/22
Y1 - 2009/5/22
N2 - T cell development depends on the coordinated interplay between receptor signaling and transcriptional regulation. Through a genetic complementation screen a transcriptional repressor, NKAP, was identified. NKAP associated with the histone deacetylase HDAC3 and was shown to be part of a DNA-binding complex, as demonstrated by chromatin immunoprecipitation. NKAP also associated with the Notch corepressor complex. The expression of NKAP during T cell development inversely correlated with the expression of Notch target genes, implying that NKAP may modulate Notch-mediated transcription. To examine the function of NKAP in T cell development, we ablated NKAP by Lckcre. Loss of NKAP blocked development of αβ but not γδ T cells, and Nkapfl/oLckcre DP T cells expressed 8- to 20-fold higher amounts of Hes1, Deltex1, and CD25 mRNA. Thus, NKAP functions as a transcriptional repressor, acting on Notch target genes, and is required for αβ T cell development.
AB - T cell development depends on the coordinated interplay between receptor signaling and transcriptional regulation. Through a genetic complementation screen a transcriptional repressor, NKAP, was identified. NKAP associated with the histone deacetylase HDAC3 and was shown to be part of a DNA-binding complex, as demonstrated by chromatin immunoprecipitation. NKAP also associated with the Notch corepressor complex. The expression of NKAP during T cell development inversely correlated with the expression of Notch target genes, implying that NKAP may modulate Notch-mediated transcription. To examine the function of NKAP in T cell development, we ablated NKAP by Lckcre. Loss of NKAP blocked development of αβ but not γδ T cells, and Nkapfl/oLckcre DP T cells expressed 8- to 20-fold higher amounts of Hes1, Deltex1, and CD25 mRNA. Thus, NKAP functions as a transcriptional repressor, acting on Notch target genes, and is required for αβ T cell development.
KW - CELLIMMUNO
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=67349217871&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349217871&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2009.02.011
DO - 10.1016/j.immuni.2009.02.011
M3 - Article
C2 - 19409814
AN - SCOPUS:67349217871
SN - 1074-7613
VL - 30
SP - 696
EP - 707
JO - Immunity
JF - Immunity
IS - 5
ER -