Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia

C. Perry, M. Pick, E. Podoly, A. Gilboa-Geffen, G. Zimmerman, E. H. Sklan, Y. Ben-Shaul, S. Diamant, H. Soreq

Research output: Contribution to journalArticlepeer-review

Abstract

Hematological changes induced by various stress stimuli are accompanied by replacement of the primary acetylcholinesterase (AChE) 3′ splice variant acetylcholinesterase-S (AChE-S) with the myelopoietic acetylcholinesterase-R (AChE-R) variant. To search for putative acetylcholinesterase-S interactions with hematopoietic pathways, we employed a yeast two-hybrid screen. The transcriptional co-repressor C-terminal binding protein (CtBP) was identified as a protein partner of the AChE-S C terminus. In erythroleukemic K562 cells, AChE-S displayed nuclear colocalization and physical interaction with CtBP. Furthermore, co-transfected AChE-S reduced the co-repressive effect of CtBP over the hematopoietic transcription factor, Ikaros. In transgenic mice, overexpressed human (h) AChE-S mRNA induced selective bone marrow upregulation of Ikaros while suppressing FOG, another transcriptional partner of CtBP. Transgenic bone marrow cells showed a correspondingly elevated potential for producing progenitor colonies, compared with controls, while peripheral blood showed increased erythrocyte counts as opposed to reduced platelets, granulocytes and T lymphocytes. AChE's 3′ alternative splicing, and the corresponding changes in AChE-S/ CtBP interactions, thus emerge as being actively involved in controlling hematopoiesis and the potential for modulating immune functions, supporting reports on malfunctioning immune reactions under impaired splice site selection.

Original languageEnglish
Pages (from-to)1472-1480
Number of pages9
JournalLeukemia
Volume21
Issue number7
DOIs
StatePublished - Jul 2007
Externally publishedYes

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