Abstract
Gene array analysis has been widely used to identify genes induced during T cell activation. Our studies identified an immediate early gene that is strongly induced in response to IL-2 in mouse T cells which we named cysteine- serine-rich nuclear protein-1 (CSRNP-1). The human ortholog was previously identified as an AXIN1 induced gene (AXUD1). The protein does not contain sequence defined domains or motifs annotated in public databases, however the gene is a member of a family of three mammalian genes that share conserved regions, including cysteine- and serine-rich regions and a basic domain, they encode nuclear proteins, possess transcriptional activation domain and bind the sequence AGAGTG. Consequently we propose the nomenclature of CSRNP-1, -2 and -3 for the family. To elucidate the physiological functions of CSRNP-1, -2 and -3, we generated mice deficient for each of these genes by homologous recombination in embryonic stem cells. Although the CSRNP proteins have the hallmark of transcription factors and CSRNP-1 expression is highly induced by IL-2, deletion of the individual genes had no obvious consequences on normal mouse development, hematopoiesis or T cell functions. However, combined deficiencies cause partial neonatal lethality suggesting that the genes have redundant functions.
Highlights
The differentiation and functions of T cells are regulated by many cytokines, including the family of interleukins (IL) sharing the common cytokine receptor c chain (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21)
Among the genes that were strongly induced by IL-2 was a new gene that we named cysteineserine-rich nuclear protein-1 (CSRNP-1)
The ortholog of cysteine- serine-rich nuclear protein-1 (CSRNP-1), AXUD1, was previously identified as a gene that is up-regulated by over-expression of AXIN1 in a human colon cancer cell line [18]
Summary
The differentiation and functions of T cells are regulated by many cytokines, including the family of interleukins (IL) sharing the common cytokine receptor c chain (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21). IL-2 plays an essential role in development of peripheral T cell populations by promoting cell survival and driving expansion of antigens-stimulated T cells. It stimulates proliferation and differentiation of B cells and augments the cytotoxic activity of NK cells [1,2]. The derivation of Stat5a/b deficient mice demonstrated that this transcription factor plays a central role in the response of peripheral T cells to IL-2 [10,11] and implicating gene regulation as a critical event. Our previous studies have identified genes such as cytokine inducible SH2 containing protein (CIS), a member of the SOCS gene family, the cytokine Oncostatin M (OSM) and GADD45c. The physiological relevance of these target genes has been explored by deriving mice in which the genes for CIS (unpublished data), GADD45c [16] and OSM [17] were deleted and somewhat remarkably none of the deletions had significant consequences to T cell development or function
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