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J. Biol. Chem., Vol. 283, Issue 25, 17652-17661, June 20, 2008

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eena Promotes Myeloid Proliferation through Stimulating ERK1/2 Phosphorylation in Zebrafish^*

Huang-Ying Le, Yong Zhang, Han Liu, Li-Heng Ma, Yi Jin, Qiu-Hua Huang, Yi Chen, Min Deng, Zhu Chen^¶, Sai-Juan Chen^¶1, and Ting Xi Liu^||2

From the Laboratory of Development and Diseases and State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 225 Chong Qing South Road, Shanghai 200025, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, 197 RuiJin Road II, Shanghai 200025, ^¶Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, and ^||Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

The EEN (extra eleven nineteen) gene is one of the fusion partners of mixed-lineage leukemia, located on chromosome 19p13. Here we cloned two een genes (designated as eena and eenb) in zebrafish, which are assigned to linkage groups 8 and 2, respectively. Whole-mount in situ hybridization assay showed that eena and eenb have overlapping but distinct expression patterns during embryogenesis. Ubiquitous or targeted overexpression of eena, but not eenb, into wild-type or transgenic embryos (green fluorescent protein-labeled myeloid progenitors) induced a significant proliferation and ectopic distribution of myeloid progenitors in the yolk sac. Using a morpholino antisense gene knockdown approach, we showed that the number of myeloid progenitors and their downstream mature myelomonocytic cells was significantly decreased in the eena- deficient embryos. Mechanistically, overexpression of eena selectively stimulated ERK phosphorylation and increased the level of transcription factor c-Fos in vitro and in vivo, whereas eena lacking the Src homology 3 domain completely abolished these effects. Furthermore, a MAPK/ERK kinase (MEK) inhibitor, PD98059, blocked the eena-induced cell proliferation and activation of ERK signaling. The results suggest that eena plays an important role in the development of the myeloid cell through activation of the ERK pathway and may provide a valuable reference for future studies of the role of EEN in leukemogenesis.

Received for publication, December 26, 2007 , and in revised form, April 14, 2008.

^* This work was supported in part by National Natural Science Foundation of China Grant 30525019, Hundred Scholars Award of Chinese Academy of Science (to T. X. L.), Chinese National High Tech Program 863 Grant 2006AA02A405, Chinese National Key Program for Basic Research 973 Grant 2004CB518600, the Key Discipline Program of Shanghai Municipal Education Commission Grant Y0201, E-Institutes of Shanghai Municipal Education Commission Grant E03003 [GenBank] , and Science and Technology Commission of Shanghai Municipality Grant 06DZ22021. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1-S3 and Figs. 1-3.

¹ To whom correspondence may be addressed: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, RuiJin Hospital, 197 RuiJin Road II, Shanghai 200025, China. E-mail: sjchen{at}stn.sh.cn.

² To whom correspondence may be addressed: Laboratory of Development and Diseases, IHS, Rm. 408, Bldg. 1, 225 South Chong Qing Road, Shanghai 200025, China. Tel.: 86-21-63857025; Fax: 86-21-63857029; E-mail: txliu{at}sibs.ac.cn.

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