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J. Biol. Chem., Vol. 279, Issue 44, 45855-45864, October 29, 2004

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A Novel Human Phosphatidylethanolamine-binding Protein Resists Tumor Necrosis Factor -induced Apoptosis by Inhibiting Mitogen-activated Protein Kinase Pathway Activation and Phosphatidylethanolamine Externalization^*

Xiaojian Wang, Nan Li¶, Bin Liu¶, Hongying Sun, Taoyong Chen¶, Hongzhe Li, Jianming Qiu, Lihuang Zhang, Tao Wan¶, and Xuetao Cao¶||

From the Institute of Immunology, Zhejiang University, Hangzhou 310031, People's Republic of China and the ^¶Institute of Immunology, Second Military Medical University, Shanghai 200433, People's Republic of China

The phosphatidylethanolamine (PE)-binding proteins (PEBPs) are an evolutionarily conserved family of proteins with pivotal biological functions. Here we describe the cloning and functional characterization of a novel family member, human phosphatidylethanolamine-binding protein 4 (hPEBP4). hPEBP4 is expressed in most human tissues and highly expressed in tumor cells. Its expression in tumor cells is further enhanced upon tumor necrosis factor (TNF) treatment, whereas hPEBP4 normally co-localizes with lysosomes, TNF stimulation triggers its transfer to the cell membrane, where it binds to Raf-1 and MEK1. L929 cells overexpressing hPEBP4 are resistant to both TNF-induced ERK1/2, MEK1, and JNK activation and TNF-mediated apoptosis. Co-precipitation and in vitro protein binding assay demonstrated that hPEBP4 interacts with Raf-1 and MEK1. A truncated form of hPEBP4, lacking the PE-binding domain, maintains lysosomal co-localization but has no effect on cellular responses to TNF. Given that MCF-7 breast cancer cells expressed hPEBP4 at a high level, small interfering RNA was used to silence the expression of hPEBP4. We demonstrated that down-regulation of hPEBP4 expression sensitizes MCF-7 breast cancer cells to TNF-induced apoptosis. hPEBP4 appears to promote cellular resistance to TNF-induced apoptosis by inhibiting activation of the Raf-1/MEK/ERK pathway, JNK, and PE externalization, and the conserved region of PE-binding domain appears to play a vital role in this biological activity of hPEBP4.

Received for publication, May 10, 2004 , and in revised form, July 9, 2004.

^* This work was supported by National Natural Science Foundation Grant 30121002, National Key Basic Research Program Grant 2001CB510002, and National High Biotechnology Development Program Grant 2002BA711A01. 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 nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AY037148.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: Inst. of Immunology, Zhejiang University, 353 Yanan Rd., Hangzhou 310031, Zhejiang, P. R. China. Fax: 86-571-8721-7329; E-mail: caoxt{at}public3.sta.net.cn.

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