Disruption of ZAS3 in mice alters NF-kappaB and AP-1 DNA binding and T-cell development.
The large zinc finger proteins, ZAS, regulate the transcription of a variety of genes involved in cell growth, development, and metastasis. They also function in the signal transduction of the TGF-beta and TNF-alpha pathways. However, the endogenous protein of a representative member, ZAS3, is rapidly degraded in primary lymphocytes, which limits the determination of its physiological function in vitro. Therefore, we have generated mice with targeted disruption of ZAS3. Oligonucleotide-based microarray analyses revealed subtle but consistent differences in the expression of genes, many of which are associated with receptor or signal transduction activities between ZAS3+/+ and ZAS3-/- thymi. Gel mobility shift assays showed altered DNA binding activities of NF-kappaB and AP-1 proteins in ZAS3-deficient tissues, including the thymus. Lymphocyte analysis suggested a subtle but broad function of ZAS3 in regulating T-cell development and activation. In CD3+ ZAS3-/- thymocytes, the CD4/ CD8 ratio was decreased and CD69 expression was decreased. In peripheral CD4+ ZAS3-/- lymphocytes we observed an increased number of memory T cells.
Allen
Carl E
CE
Department of Pediatrics and Center for Cell and Developmental Biology, Columbus Children's Research Institute, Columbus, OH 43205, USA.
Richards
John
J
Muthusamy
Natarajan
N
Auer
Herbert
H
Liu
Yang
Y
Robinson
Michael L
ML
Barnard
John A
JA
Wu
Lai-Chu
LC
D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C497203:ZAS3 protein, mouse; D004247:DNA