Modulation of Fos-mediated AP-1 transcription by the promyelocytic leukemia protein

被引:44
作者
Vallian, S
Gäken, JA
Gingold, EB
Kouzarides, T
Chang, KS [1 ]
Farzaneh, F
机构
[1] Univ Texas, MD Anderson Cancer Ctr, Div Lab Med, Houston, TX 77030 USA
[2] Univ London Kings Coll, Sch Med & Dent, Dept Mol Med, London SE5 9NU, England
[3] Univ Cambridge, Wellcome CRC Inst, Cambridge CB2 1QR, England
基金
英国惠康基金;
关键词
AP-1; PML; Fos; APL; transcription;
D O I
10.1038/sj.onc.1201837
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The growth and transformation suppressor function of promyelocytic leukemia (PML) protein are disrupted in acute promyelocytic leukemia (APL) as a result of its fusion to the RAR alpha gene by t(15;17) translocation. There is significant sequence homology between the dimerization domain of PML and the Fos family of proteins, which imply that PML may be involved in AP-1 activity. Here we show that PML can cooperate with Fos to stimulate its AP-1-mediated transcriptional activity. Cotransfection of PML with GAL4/Fos strongly induced Fos-mediated activation of GAL4-responsive reporters, indicating a functional interaction between Fos and PML in vivo. Deletion analysis of Fos and PML demonstrated that the intact C-terminal domain of Fos (containing the dimerization domain), and the RING-finger, B1 box and nuclear localization domains of PML are involved in the cooperative activity of Fos and PML. Immunoprecipitation and electrophoretic mobility shift assay showed that PML is associated with the AP-1 complex. PMLRAR alpha was also found to enhance the transcriptional activity of GAL4/Fos. The addition of retinoic acid abrogated the PMLRAR alpha, but not PML-induced stimulation of GAL4/Fos activity in a dose-dependent manner. This study demonstrated that PML is involved in the AP-1 complex and can modulate Fos-mediated transcriptional activity, which may contribute to its growth suppressor function.
引用
收藏
页码:2843 / 2853
页数:11
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