Abstract
BackgroundThe LAT gene encodes an intracellular adaptor protein that links cell-surface receptor engagement to numerous downstream signalling events, and thereby plays an integral role in the function of cell types that express the gene, including T cells, mast cells, natural killer cells, and platelets. To date, the mechanisms responsible for the transcriptional regulation of this gene have not been investigated.ResultsIn this study we have mapped the transcriptional start sites for the human LAT gene and localized the 5' and 3' boundaries of the proximal promoter. We find that the promoter contains both positive and negative regulatory regions, and that two binding sites for the Ets family of transcription factors have a strong, positive effect on gene expression. Each site binds the Ets family member Elf-1, and overexpression of Elf-1 augments LAT promoter activity. The promoter also contains a Runx binding site adjacent to one of the Ets sites. This site, which is shown to bind Runx-1, has an inhibitory effect on gene expression. Finally, data is also presented indicating that the identified promoter may regulate cell-type specific expression.ConclusionCollectively, these results provide the first insights into the transcriptional regulation of the LAT gene, including the discovery that the Ets transcription factor Elf-1 may play a central role in its expression.
Highlights
The LAT gene encodes an intracellular adaptor protein that links cell-surface receptor engagement to numerous downstream signalling events, and thereby plays an integral role in the function of cell types that express the gene, including T cells, mast cells, natural killer cells, and platelets
The data presented suggests that the identified promoter region may mediate cell-type specific expression of the LAT gene. These results provide the first insights into the transcriptional regulation of the LAT gene, which encodes an essential adaptor protein linking cell-surface receptors to critical downstream signaling events
The LAT gene contains multiple transcription start sites As an initial step in the identification and characterization of the LAT promoter, we mapped the transcription start site(s) for the human LAT gene using RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE) and poly(A) RNA isolated from Jurkat T cells or human thymus
Summary
The LAT gene encodes an intracellular adaptor protein that links cell-surface receptor engagement to numerous downstream signalling events, and thereby plays an integral role in the function of cell types that express the gene, including T cells, mast cells, natural killer cells, and platelets. The essential role of LAT in TCR signaling has been revealed through the study of mutant Jurkat T cell lines that fail to express the LAT gene [5,6]. These LAT-deficient T cells display a number of signaling defects that prevent T cell activation and effector cell function.
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