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 language | English |
|---|---|
| Pages (from-to) | 1472-1480 |
| Number of pages | 9 |
| Journal | Leukemia |
| Volume | 21 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2007 |
Bibliographical note
Funding Information:This work was supported by grants from the Bat Sheva de Rothschild Career Development Award, the Israel Ministry of Health (to CP), United States–Israel Binational Science Foundation (BSF no. 2003028-01 to CP and HS), the Israeli Ministry of Science Grant (to HS and CP), the EU’s Alternative Splicing Network of Excellence (no. 518238) and the EU’s STREP (LSHG-CT no. 2006-037277) and the Israel/Germany Biodisc Program (to HS). We are grateful to Dr M Crossley (Sydney, Australia) for Ikaros and mCtBP vectors, to Dr R Goodman (Portland, OR) for the hCtBP1 vector and to K Ofek and D Toiber (Jerusalem) for assistance in experiments. This work was done at The Hebrew University of Jerusalem and the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.