Abstract
Ras-related nuclear protein (Ran) is a Ras family GTPase, and its documented functions are the regulation of DNA replication, cell cycle progression, nuclear structure formation, RNA processing and exportation, and nuclear protein importation. In this study, we performed detailed mapping of Ran expression during mouse ontogeny using in situ hybridization. High Ran expression was found in various organs and tissues including the thymus cortex and spleen white pulp. Ran was induced in T cells 24 h after their activation. The function of Ran in the immune system was investigated using Ran transgenic (Tg) mice. In Ran Tg T cells, there was compromised activation marker expression, lymphokine secretion, and proliferation upon T cell receptor activation in vitro when compared with wild type T cells. Tg mice also manifested defective delayed type hypersensitivity in vivo. Upon PMA and ionomycin stimulation, Tg T cells were defective in nuclear accumulation of AP-1 factors (c-Jun and c-Fos) but not NF-kappaB family members. Our experiments showed that Ran had important regulatory function in T cell activation. One of the possible mechanisms is that intracellular Ran protein levels control the nuclear retention for selective transcription factors such as c-Jun and c-Fos of AP-1, which is known to be critical in T cell activation and proliferation and lymphokine secretion.
Highlights
Chromosomal condensation) [4], and the complex performs critical functions in many cellular events, such as DNA replication [5], cell cycle progression [5], nuclear structure [6, 7], RNA processing and exportation [8], and nuclear protein importation [9]
The cortex (Cx) but not the medulla (Me) was highly positive (Fig. 2A); in the spleen, related nuclear protein (Ran) signals were concentrated in the white pulp (WP) but not in the red pulp (RP) (Fig. 2B)
Ran is involved in DNA replication and cell cycle progression
Summary
Chromosomal condensation) [4], and the complex performs critical functions in many cellular events, such as DNA replication [5], cell cycle progression [5], nuclear structure [6, 7], RNA processing and exportation [8], and nuclear protein importation [9]. Ran resides in chromosome 5 (GenBankTM accession number NM_009391). Multiple Ran isoform genes are located in different genomic loci in mice [10]. Ran/M2, is coded by a gene in chromosome 7 (GenBank accession number: NM_009028); Ran and Ran/M2 share 94.6% identity in the nucleotide coding sequence and 94.0% identity and 98.1% similarity (allowing amino acid substitution) in their peptide sequences [11]. Consistent with the role of Ran in protein importation into nuclei, IFN-␥-dependent STAT-1 translocation to nuclei depends on Ran and its GTPase activity [13]. Ran transgenic (Tg) T cells presented compromised functions and reduced c-Jun and c-Fos nuclear import upon activation. Our results suggest that the Ran expression level controls the nuclear presence of selective transcription factors, which in turn modulate T cell immune responses
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