Ran overexpression leads to a compromised transcription factor nuclear translocation and diminished T-cells response to TCR activation (35.8)

Abstract

Abstract Ran (Ras-related nuclear protein) 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 various organs and tissues including the thymus cortex and spleen white pulp. Ran was induced in T cells 24 hours after their activation. Ran's function in the immune system was investigated. In transgenic T cells with actin promoter-driven Ran expression, there was compromised activation marker expression, lymphokine secretion, and proliferation upon T cell receptor (TCR) activation in vitro, compared with wild-type T cells. At the molecular level, transgenic T cells were defective in nuclear factor kappa-B (NFκB), activator protein 1 (AP-1) and nuclear factor of activated T cells (NFAT) nuclear translocation. Our experiments showed, for the first time, that Ran has important regulatory function in T-cell activation, and such function is probably related to its role in nuclear import of critical transcription factors.