ARTICLES

Cell Research (2004); 14(6):473-479

Regulation of alternative splicing of Bcl-x by IL-6, GM-CSF and TPA

Chang You LI¹, Jia You CHU^1,*, Jian Kun YU¹, Xiao Qin HUANG¹, Xiao Juan LIU¹, Li SHI¹, Yan Chun CHE¹, Jiu Yong XIE^2,*

¹Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China.
²Department of Physiology, Faculty of Medicine, University of Manitoba, 420 BMSB, 730 William Ave., Winnipeg, MB R3E 3J7, Canada.

Received, Feb 18, 2004    Revised, Sep 24, 2004    Accepted, Oct 5, 2004

Correspondence: Jia You CHU chujy@public.km.yn.cn and Jiu Yong XIE xiej@cc.umanitoba.ca

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Abstract

The splicing of many alternative exons in the precursor messenger RNA (pre-mRNA) is regulated by extracellular factors but the underlying molecular bases remain unclear. Here we report the differential regulation of Bcl-x pre-mRNA splicing by extracellular factors and their distinct requirements for pre-mRNA elements. In K562 leukemia cells, treatment with interleukin-6 (IL-6) or granulocyte-macrophage colony stimulating factor (GM-CSF) reduced the proportion of the Bcl-xL variant mRNA while treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) had no effect. In U251 glioma cells, however, TPA efficiently increased the Bcl-xL level. These regulations were also seen for a transfected splicing reporter mini-gene. Further analyses of deletion mutants indicate that nucleotides 1-176 of the downstream intron are required for the IL-6 effect, whereas additional nucleotides 177-284 are essential for the GM-CSF effect. As for the TPA effect, only nucleotides 1-76 are required in the downstream intron. Thus, IL-6, GM-CSF and TPA differentially regulate Bcl-x splicing and require specific intronic pre-mRNA sequences for their respective effects.

Keywords: alternative splicing, bcl-x gene, cytokine, TPA, pre-mRNA element.