The Study Of The Mechanism Of The CSF-1 Gene Transcription Promoted By L-selectin Crosslinking

L-selectin, a member of selectin family, constitutively expressed on all kinds of leukocytes, plays a fundamental role in the immune system by mediating lymphocyte homing and in the recruitment of leukocytes to inflammatory sites. Except for its role in adhesion, L-selectin can also function as a signal transduction molecule. Crosslinking of human L-selectin with its antibody leads to cell shape change, cytoskeleton reorganization, superoxide generation, increased cytokine gene transcription, and activation of intracellular protein pathways. These studies indicate that engagement of L-selectin results in the activation of signaling pathways in Jurkat cells, which probably relative to different kinase activity and nuclear transcription factor activation.c-Abl, a non-receptor protein tyrosine kinase, has been shown to be very important for cell signal transduction. c-Abl contains a catalytic domain, polyproline rich regions, and SH2 and SH3 domains. Additionally, the carboxyl terminus of c-Abl contains nuclear localization and nuclear export signals (NLS and NES), as well as F- and G-actin-binding domains. The mammalian c-Abl can shuttle between the nuclear and cytoplasmic compartments. Nuclear c-Abl kinase plays a role in transcriptional regulation, particularly in response to DNA damage and apoptosis.In this study, we focus on the function of c-Abl kinase in the signaling transduction induced by L-selectin ligation by regulating CSF-1 gene transcription . Our results demonstrated that overexpression of WT c-Abl kinase increased CSF-1 gene transcriptional activity. Alternatively, CSF-1 transcription was blockaded by STI571 incubation as well as by overexpression of the KD mutant of c-Abl, suggesting that c-Abl kinase regulates CSF-1 gene transcription dependenting on its kinase activity. We found that c-Abl kinase can be recruited to the nucleus following L-selectin ligation, and the nuclear c-Abl kinase can phosphorylate c-Jun and regulate AP-1 activity. Furthermore, the activated c-Abl kinase associates with AP-1 and forms a complex in the CSF-1 promoter region to regulate CSF-1 gene transcription in the L-selectin ligation activated Jurkat cells. These results indicate that nuclear c-Abl kinase can activate CSF-1 gene transcription by regulating AP-1 activity in the signaling events induced by L-selectin ligation.