Developmental regulation of lck gene expression in T lymphocytes.

Abstract

Summary'Abbreviation used in this paper. UTR, untranslated region . In the mouse and human, mRNA transcripts encoding the lymphocyte-specific protein tyrosine kinase p56ikk are derived from two separate promoters resulting in heterogeneity in the 5' untranslated region sequence. The proximal promoter lies just 5' to the coding region for the gene and is active only in thymocytes . In contrast, the distal promoter lies 34 kilobases (kb) 5' in the human, and is active both in thymocytes and mature peripheral T cells . As previously reported, transgenic mice bearing functional proximal promoter sequence juxtaposed with the SV40 large T antigen gene invariably develop lymphoid tumors confined to the thymus. In the current work, transgenic mice bearing a 2 .6-kb fragment of the human distal promoter fused to the SV40 large T antigen gene express large T antigen in thymocytes and in peripheral lymphoid cells, and develop tumors of both the thymus and the peripheral lymphoid organs . The ability of the human distal promoter to function appropriately in transgenic mice is consistent with the strong similarity observed between the mouse and human distal promoter sequences . With the exception of a single short interval that serves as a target for binding of nuclear factors, significant sequence similarity is not seen when the distal and proximal promoter sequences are compared. Hence, developmentally regulated, lineage-specific transcription of the Ick gene is mediated by distinct promoter sequences that appear to be capable of functioning independently.

Caspase Enzyme Activity Is Not Essential for Apoptosis During Thymocyte Development

“…The high p35 expression levels in lck-p35 transgenic thymocytes do not persist in peripheral lymphoid tissues (data not shown), which is in accord with the known down-regulation of endogenous lck proximal promoter activity in mature T cells (32). Analysis of freshly isolated tissues showed that thymus, spleen, and lymph nodes of lck-p35 transgenic mice were indistinguishable from normal control mice.…”

The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

“…As described previ-ously, exons 16 and 17 of the IRE1␣ gene are floxed in these mice, resulting in a truncated, inactive form of IRE1␣ protein (15). The Cre DNA recombinase is mediated by the Lck promoter, which drives gene expression during thymic development, and the gene is specific for T cells, allowing for a targeted deletion of IRE1␣ gene during T cell development (23,24). Immunoblotting analysis detected the mutant form of IRE1␣ protein in naïve T cells from the IRE1␣ f/f Lck-Cre ϩ mice ( Fig.…”

Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation.

“…In these constructs^ Tpl-2 was placed under the control of the proximal Lck promoter and was expressed specifically in thymocytes (Abraham et al 1991a,b;Wildin et al 1991). Forty-eight transgenic founders, 24 with the wild-type and 24 with the truncated construct, were established.…”

“…Tpl-2 cDNAs containing exon IB were placed under the control of the proximal Lck promoter that is specifically active in thymocytes (Abraham et al 199la,b;Wildin et al 1991). An SV40 large T antigen polyadenylation signal was inserted 3' of the TpI-2 cDNA to ensure proper termination of transcription.…”