Regulation of the human LAT gene by the Elf-1 transcription factor

In 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.Collectively, 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.The LAT gene encodes a 36–38 kD transmembrane protein that connects various cell surface receptors to downstream signaling events. Following receptor engagement, LAT becomes heavily tyrosine phosphorylated and subsequently binds a number of proteins containing SH2 domains, including members of the Grb2 family (Grb2, Gads, Grap) and phospholipase C-γ (PLC-γ) [1,2]. The interaction of Grb2, PLC-γ and other proteins with LAT facilitates their activation and leads to additional biochemical events required for a productive cellular response, including activation of the Ras-MAPK signaling pathway and an elevation in intracellular calcium levels [1,2].One receptor type whose engagement results in LAT tyrosine phosphorylation is the T cell receptor (TCR) [3,4]. 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. An ana