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Role of Krüppel-Like Factor 4 and Its Binding Proteins in Vascular Disease

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Role of Krüppel-Like Factor 4 and Its Binding Proteins in Vascular Disease 402 Journal of Atherosclerosis and Thrombosis Vol.21, No.5 Review Role of Krüppel-Like Factor 4 and its Binding Proteins in Vascular Disease Tadashi Yoshida and Matsuhiko Hayashi Apheresis and Dialysis Center, School of Medicine, Keio University, Tokyo, Japan Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays a key role in cellular differentiation and proliferation during normal development and in various diseases, such as cancer. The results of recent studies have revealed that KLF4 is expressed in multiple vascular cell types, including phenotypically modulated smooth muscle cells (SMCs), endothelial cells and monocytes/ macrophages and contributes to the progression of vascular diseases by activating or repressing the transcription of multiple genes via its associations with a variety of partner proteins. For example, KLF4 decreases the expression of markers of SMC differentiation by interacting with serum response factor, ELK1 and histone deacetylases. KLF4 also suppresses SMC proliferation by associating with p53. In addition, KLF4 enhances arterial medial calcification in concert with RUNX2. Furthermore, endothelial KLF4 represses arterial inflammation by binding to nuclear factor-κB. This article sum- marizes the role of KLF4 in vascular disease with a particular focus on in vivo studies and reviews recent progress in our understanding of the regulatory mechanisms involved in KLF4-mediated gene transcription. J Atheroscler Thromb, 2014; 21:402-413. Key words: Krüppel-like factor, Smooth muscle, Endothelium, Serum response factor, Nuclear factor-κB, RUNX2 ing transcription factors (reviewed in2-4)). The name Introduction “Krüppel” is derived from the Drosophila protein Vascular proliferative diseases, such as atheroscle- krüppel (meaning “cripple” in German), which shares rosis and restenosis after percutaneous coronary inter- homology of proteins to DNA-binding domains5, 6). vention, are major causes of mortality in Westernized Krüppel-deficient embryos in Drosophila die with con- societies. Such conditions are recognized to be com- sequences of abnormal thoracic and abdominal seg- plex disorders involving multiple cell types, including mentation and thus appeared “crippled.” The unique smooth muscle cells (SMCs), endothelial cells (ECs), feature of the KLF family is the presence of three 1) lymphocytes and monocytes/macrophages . For the highly conserved cysteine 2/histidine 2 (C 2H 2)-type advancement of therapeutic and preventive approaches, zinc-fingers located at the carboxyl terminus of the it is important to understand the molecular and cellu- protein, while the non-DNA-binding regions are lar mechanisms underlying the progression of vascular highly divergent, thus enabling them to carry out their diseases in each cell type. individual functions. There are currently 17 known The mammalian Krüppel-like factor (KLF) fam- KLF family members, with KLF4 being one of the ily is a subclass of zinc-finger containing DNA-bind- most fascinating, having received increased attention in recent years due to its ability to generate induced Address for correspondence: Tadashi Yoshida, Apheresis and pluripotent stem cells in combination with OCT3/4, Dialysis Center, School of Medicine, Keio University, 35 7, 8) Shinanomachi, Shinjuku, Tokyo 160-8582, Japan SOX2 and c-MYC . E-mail: [email protected] KLF4 was formerly known as gut-enriched KLF, Received: December 6, 2013 GKLF9), or epithelial zinc finger, EZF10), and plays a Accepted for publication: January 19, 2014 key role in cellular differentiation and proliferation KLF4 in Vascular Disease 403 during normal development11-15) as well as in various as SM α-actin (ACTA2), SM-myosin heavy chain diseases, such as cancer13, 16, 17). Although KLF4 is (MYH11), SM22α (TAGLN) and h1-calponin, in abundantly expressed in the colon, testis and lungs9), order to maintain vessel tone26, 27). The transcription it is also detectable in the vascular system. Indeed, of these SMC differentiation marker genes is con- human KLF4 cDNA was first cloned from a human trolled by common cis-elements, including multiple 10) umbilical vein EC cDNA library , and KLF4 has CC(A/T)6GG (CArG) elements and a transforming been shown to be constitutively expressed in ECs in growth factor-β control element (TCE)26-35). For the aorta and pulmonary arteries and veins18). In con- example, the Acta2 gene and Myh11 gene have three trast, KLF4 is not expressed in differentiated SMCs in CArG elements and a single TCE, respectively, adult vessels, although it is induced in phenotypically whereas the Tagln gene contains two CArG elements modulated SMCs following vascular injury 19, 20). and one TCE in its promoter-enhancer region. Studies Moreover, the results of recent studies have demon- using transgenic mice harboring the LacZ reporter strated that KLF4 is also expressed in monocytes/mac- gene driven by the promoter-enhancer regions of rophages21-23). As such, KLF4 is expressed in multiple SMC differentiation marker genes have demonstrated cells that participate in the development of vascular that multiple CArG elements as well as TCE are diseases, although its role has not yet been fully deter- required to recapitulate the expression patterns of the mined. This review article summarizes the contribu- endogenous gene29-35). The binding factor for CArG tion of KLF4 to the development of vascular diseases, elements is serum response factor (SRF), which regu- with a particular focus on in vivo studies, and consid- lates the expression of SMC differentiation marker ers recent advances in our understanding of the molec- genes by cooperating with its co-activator, myocardin ular mechanisms whereby KLF4 exerts multiple effects (MYOCD)36-39), or its co-repressor, phosphorylated by interacting with various partner proteins. For a ELK140-42). While SRF is ubiquitously expressed and it more comprehensive review of KLF family members itself does not activate the transcription of SMC dif- and/or their role in transcriptional regulation in vas- ferentiation marker genes in SMCs, MYOCD is selec- cular diseases, the reader should refer to several excel- tively expressed in SMCs and cardiac muscle and lent review articles1-4, 24-28). induces the transcription of multiple CArG-contain- ing SMC differentiation marker genes via homodi- merization36-39, 43). Of interest, Myocd-deficient mice KLF4 in SMCs exhibit no vascular SMC differentiation and die by Although the primary function of SMCs is con- embryonic day 10.5, although it is possible that this traction in order to maintain vessel tone, SMCs also early embryonic lethality is secondary to defects in the retain considerable plasticity, allowing them to exert extraembryonic circulation and/or pericardial effu- multiple effects in response to changes in local envi- sion44). In addition, studies using Myocd chimeric ronmental cues26, 27). For example, in association with knockout mice have shown that MYOCD is dispens- vascular injury or atherosclerotic lesion formation, able for the development of vascular SMCs45, 46). Stud- SMCs undergo a process often referred to as pheno- ies conducted to date suggest that MYOCD is not typic modulation or phenotypic switching, character- necessarily required for SMC differentiation, although ized by a dramatic increase in the rate of proliferation, it plays a critical role in the expression of CArG ele- migration and synthesis of extracellular matrix pro- ment-containing SMC differentiation marker genes. teins in addition to a decreased expression of SMC- On the other hand, ELK1 is expressed widely and specific/-selective differentiation markers. The results phosphorylated in response to platelet-derived growth of studies conducted by our laboratory and others factor-BB (PDGF-BB) and/or oxidized phospholipids, have revealed KLF4 to be a critical transcriptional reg- thus mediating the repression of SMC differentiation ulator of phenotypic switching of SMCs by interact- marker genes in cultured SMCs40-42). MYOCD and ing with various proteins. The multiple roles of KLF4 ELK1 have a structurally related SRF-binding motif in the functions of SMCs will be reviewed in this sec- and thus compete for the common docking region of tion. SRF40). The balance between MYOCD and phosphor- ylated ELK1 is one of the determinants regulating the KLF4 Suppresses the Expression of SMC Differen- transcriptional activity of SMC differentiation marker tiation Markers by Interacting with ELK1, Serum genes. Response Factor and/or p65 The trans-acting factor for TCE is KLF4. Adam Differentiated SMCs express a unique repertoire et al.34) identified KLF4 as a binding factor for the of contractile proteins and signaling molecules, such TCE located within the Tagln promoter using a yeast 404 Yoshida and Hayashi A B Fig.1. KLF4 suppresses the expression of SMC differentiation markers by interacting with ELK1, SRF and HDACs A: MYOCD, SRF and multiple CArG elements positively regulate the tran- scription of SMC differentiation marker genes in SMCs. SRF binds to the CArG element as a dimer, while MYOCD is a non-DNA binding co-factor for SRF. The homodimerization of MYOCD potently activates SMC differentia- tion marker genes. B: The transcription of SMC differentiation marker genes is negatively controlled by vascular injury in vivo and/or treatment with PDGF- BB and oxidized phospholipids in cultured SMCs. In response to stimuli elicit- ing SMC phenotypic switching, KLF4 is induced and binds to the TCE within the promoter region of SMC differentiation
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