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WDR26: a Novel G[Bgr]-Like Protein, Suppresses MAPK Signaling Pathway

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WDR26: a Novel G[Bgr]-Like Protein, Suppresses MAPK Signaling Pathway http://www.paper.edu.cn Journal of Cellular Biochemistry 93:579–587 (2004) WDR26: A Novel Gb-Like Protein, Suppresses MAPK Signaling Pathway Ying Zhu,1 Yuequn Wang,1 Chunzhi Xia,2 Dali Li,1 Yongqing Li,1 Weiqi Zeng,1 Wuzhou Yuan,1 Hui Liu,1 Chuanbing Zhu,1 Xiushan Wu,1 and Mingyao Liu1,2* 1College of Life Sciences, Hunan Normal University, Changsha, 410081 Hunan, China 2Alkek Institute of Biosciences and Technology, and Department of Medical Biochemistry and Genetics, Texas A&M University System Health Science Center, Houston, Texas 77030 Abstract WD40 repeat proteins play important roles in a variety of cellular functions, including cell growth, proliferation, apoptosis, and intracellular signal transduction. Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes in cell signal transduction connecting cell-surface receptors to critical regulatory targets within cells and control cell survival, adaptation, and proliferation. Previous studies revealed that G-protein coupled receptors (GPCRs) play important roles in the signal transduction from extracellular stimuli to MAPKs and the WD40-containing Gb proteins as well as Gb-like proteins are involved in the stimulation and regulation of the MAPK signaling pathways. Here we report the identification and characterization of a novel human WD40 repeat protein, WD40 repeat protein 26 (WDR26). The cDNA of WDR26 is 3,729 bp, encoding a Gb-like protein of 514 amino acids in the cytoplasm. The protein is highly conserved in evolution across different species from yeast, Drosophila, mouse, to human. Northern blot analysis indicates that WDR26 is expressed in most of the examined human tissues, especially at a high level in skeletal muscle. Overexpression of WDR26 in the cell inhibits the transcriptional activities of ETS proteins, ELK-1 and c-fos serum response element (SRE), mediated by MEKK1. These results suggest that WDR26 may act as a negative regulator in MAPK signaling pathway and play an important role in cell signal transduction. J. Cell. Biochem. 93: 579–587, 2004. ß 2004 Wiley-Liss, Inc. Key words: WD40 repeat protein; WD-40; Gb-like protein; WDR26; MAPK signaling pathway Members of the WD-40 family of proteins, heterotrimeric GTP-binding proteins, play a including the well-known Gb subunits of variety of roles in intracellular signaling, RNA processing and degradation, gene expression, vesicular traffic and fusion, cytoskeletal assem- bly, and the cell cycle as described in earlier reviews [Smith et al., 1999; Yu et al., 2000; Cabrera-Vera et al., 2003]. All proteins within Abbreviations used: MAPK, mitogen-activated protein the WD-40 family contain repeating sequences kinase; ERK, extracellular signal-related kinases; JNK, that are separated by approximately 40 amino Jun amino-terminal kinases; GPCRs, G-protein coupled acids. Each WD-40 repeat consists of two receptors; WDR26, WD40 repeat protein 26; MAPKK, signature sites: a poorly conserved site A MKK, or MEK, MAPK kinase; MAPKKK, MAPKK kinase; MEKK MEK kinase; EST, expressed sequence tags; WDR, containing a glycine and histidine (GH) pair, WD40 repeat protein; SRE, c-fos serum response element; and a well-conserved site B containing a SRF, serum response factor; BSA, bovine serum albumin; tryptophan and aspartate (WD) pair. Although DMEM, Dulbecco’s modified Eagle’s sodium. each protein contains four to eight WD-40 Ying Zhu, Yuequn Wang, and Xiushan Wu contributed repeating motifs, the separating distance and equally to the work. the actual sequence of individual repeats are Grant sponsor: Hunan Normal University (Special Profes- high variable. The functional diversity of WD- sorships); Grant sponsor: National Natural Science Foun- dation of China. 40 proteins suggests that WD-40 motifs may *Correspondence to: Mingyao Liu, PhD, College of Life not necessarily confer any particular function Sciences, Hunan Normal University, Changsha, Hunan while it may contributes to the formation of 410081, China. E-mail: [email protected] anti-parallel b-strands that stabilize the three- Received 26 March 2004; Accepted 29 April 2004 dimmensional b-propellers [Sondek et al., 1996; DOI 10.1002/jcb.20175 Smith et al., 1999]. ß 2004 Wiley-Liss, Inc. 转载 中国科技论文在线 http://www.paper.edu.cn 580 Zhu et al. Mitogen-activated protein kinases (MAPK) protein, WD40 repeat protein 26 (WDR26). are common components in signal transduction Northern blot analysis demonstrates that this connecting cell-surface receptors to critical gene is expressed in most of the human tissues, regulatory targets within cells and control a and especially at high levels in fetal brain and wide range of processes from the cell-cycle skeletal muscle of both fetal and adult stages. arrest and mating in yeast to cell proliferation This cytoplasmic protein contains five Gb-like and differentiation in metazoans (reviewed by WD40 repeats similar to hPIP1 and have Feng et al., 1998; Cobb, 1999; Kyriakis and similar sequence to WD40 repeat protein Avruch, 2001). The MAPK cascades are regu- 5 (WDR5), which can be induced by BMP-2 lated through three-tiered cascades composed of and dramatically accelerate the program of a MAPK, MAPK kinase (MAPKK, MKK, or osteoblastic differentiation [Gori et al., 2001]. MEK) and a MAPKK kinase or MEK kinase Transfection of WDR26 in mammalian cells can (MAPKKK or MEKK), which work in series and significantly suppress the transcriptional acti- comprise a module (reviewed by English et al., vation of MEKK-mediated SRE and ELK-1. 1999). In mammals there are at least four These results suggest that this new Gb-like distinct groups of MAPKs: extracellular sig- WD40 repeat protein may act as a repressor in nal-related kinases (ERK)-1/2, Jun amino- MAPK signaling pathway to mediate cellular terminal kinases (JNK1/2/3), p38 proteins functions. (p38 a/b/g), and ERK5, which are activated by specific MAPKKs and phosphorylate specific MATERIALS AND METHODS cellular targets. As reviewed by Chang and Cloning the Full-Lenghth cDNA and Karin [2001], one of the most explored targets of Bioinformatics Analysis MAPK signaling modules is transcription fac- tors, such as c-jun, Elk-1 which regulates tran- In order to identify novel Gb-like proteins in scription immediate early gene expression cell signal transduction, we used the consensus through binding to the serum response element sequence of WD40 region as the subject to (SRE) [Gille et al., 1995]. For example, most search human expressed sequence tags (EST) MAPKs phosphorylate ETS transcription fac- database with BLASTx algorithm (http:// tors that are involved in induction of fos www.ncbi.nlm.nih.gov/BLAST). Through com- genes, whose products heterodimerize with bined BLAST search and PCRs analysis as Jun proteins to form activation protein 1 (AP-1) previously described [Zeng et al., 2002], we complexes [Treisman, 1996]. Presumably each identified four overlapping ESTs—AW968761, MAPKKK confers responsiveness to distinct BG825203, BI757309, and BF971220, belong- stimuli, such as growth factors, hormones, ing to the same novel gene. A heart cDNA stress, and inflammation. library was constructed as PCR template with The multiplicity of both GPCR and MAPK the kits obtained from TAKARA1.50-RACE signaling pathways suggests the activities of PCR was performed with TAKARA 50-RACE both G-protein coupled receptors (GPCRs) and Core Kit to confirm the 50 terminus of WDR26. MAPKs is tightly regulated, depending on Jellyfish 1.4 was used to find the open reading cooperation of a number of activators and frame (ORF) and the deduced translated pro- suppressors. Although, we have known a lot duct. Then, the coding sequence was cloned about the activation process from receptors to from human heart library. All the primers and MAPKs, the knowledge on the mechanism of reaction conditions for these PCRs are listed in negative regulation is far from well developed. Table I and these PCR products were confirmed Recently, our laboratory identified a human by sequencing (Biotech1). For mammalian PAK1-interacting protein, hPIP1, which is a expression, the WDR26 ORF was subcloned negative regulator of p21-activated protein into the BamHI site of pCMV-tag2C (Strata- kinase (PAK). Overexpression of hPIP1 can gene1). The full-length sequence of WDR26 inhibit the Cdc42-stimulated PAK kinase activ- was submitted to GeneBank with an accession ity as well as PAK-mediated JNK and NF-kB number AY304473. signaling pathways through interaction with BLASTn (http://www.ncbi.nlm.nih.gov/BLAST) the N-terminal regulatory domains of PAK1 and Pfam 9.0 [Bateman et al., 2002] were used [Xia et al., 2001b]. Here we report the identifica- to analyze genomic structure and the pro- tion and characterization of a novel Gb-like tein domain, respectively. The homologues of 中国科技论文在线 http://www.paper.edu.cn WDR26 Suppresses MAPK Signaling Pathway 581 TABLE I. Sets of Specific Oligonucleotide Primers and PCR Conditions Primers Sequences Programs Cycles E1 50-GCAAGAGTCAGGATGTCG-30 948C for 30 s; 508C for 30 s; 728C for 1 min 30 E2 50-CCAAAGCTCAGAGCAGTC-30 E3 50-GGAGGCACTTCAAGTTCTAC-30 948C for 30 s; 508C for 30 s; 728C for 1 min 30 E4 50-TCCATCACTCAAGCACCA-30 E5 50-ACTGGAGGTCAGCGTGGGC-30 948C for 30 s; 528C for 30 s; 728C for 1 min 30 E6 50-CGGGCTTCAGAAATGGTT-30 RT1 50-TCAGCGGCGTCAAT-30 308C for 10 min; 508C for 60 min; 808C for 2 min 1 S1 50-CGGAATTTGGTAGCAGAAGG-30 948C for 4 min; 568C for 1 min; 728C for 1 min 30 A1 50-CATGGAAGGAGACTGGGATAAG-30 S2 50-CAGTCTGGTTGAGCCCTAA-30 948C for 1 min; 588C for 1 min; 728C for 1 min 30 A2 50-GGCACTTCAAGTTCTACGC-30 Os 50-CAGGATCCCCGCCTCCTCTTCCT-30 948C for 30 s; 558C for 30 s; 728C for 2 min 30 Oa 50-GGATCCCAACTATCCATGCTACTGCAT-30 E1 to E6 are for expressed sequence tags (ESTs) analysis (E1 at the 3 terminus of AW968761 and E2 at 5 terminus of BG825203, E3 at the 3 terminus of BG825203 and E4 at the 5 terminus of BI757309, E5 at the 3 terminus of BI757309, and E6 at the 5 terminus of BF971220).
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