Báo cáo khoa học: Nuclear actin and actin-binding proteins in the regulation of transcription and gene expression docx

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Báo cáo khoa học: Nuclear actin and actin-binding proteins in the regulation of transcription and gene expression docx

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REVIEW ARTICLE Nuclear actin and actin-binding proteins in the regulation of transcription and gene expression Bin Zheng1, Mei Han1, Michel Bernier2 and Jin-kun Wen1 Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang, China Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA Keywords actin dynamics; actin-binding protein; chromatin remodeling; gene regulation; muscle-specific gene; nuclear actin; nuclear receptor; ribonucleoprotein; RNA polymerases; transcription complex Correspondence J.-k Wen, Department of Biochemistry and Molecular Biology, Hebei Medical University, No 361, Zhongshan East Road, Shijiazhuang 050017, China Fax: +86 311 866 96180 Tel: +86 311 862 65563 E-mail: wjk@hebmu.edu.cn (Received 12 January 2009, revised 20 February 2009, accepted 26 February 2009) doi:10.1111/j.1742-4658.2009.06986.x Nuclear actin is involoved in the transcription of all three RNA polymerases, in chromatin remodeling and in the formation of heterogeneous nuclear ribonucleoprotein complexes, as well as in recruitment of the histone modifier to the active gene In addition, actin-binding proteins (ABPs) control actin nucleation, bundling, filament capping, fragmentation and monomer availability in the cytoplasm In recent years, more and more attention has focused on the role of actin and ABPs in the modulation of the subcellular localization of transcriptional regulators This review focuses on recent developments in the study of transcription and transcriptional regulation by nuclear actin, and the regulation of muscle-specific gene expression, nuclear receptor and transcription complexes by ABPs Among the ABPs, striated muscle activator of Rho signaling and actin-binding LIM protein regulate actin dynamics and serum response factor-dependent muscle-specific gene expression Functionally and structurally unrelated cytoplasmic ABPs interact cooperatively with nuclear receptor and regulate its transactivation Furthermore, ABPs also participate in the formation of transcription complexes Actin is a major component of the cytoskeleton and plays a critical role in all eukaryotic cells The actin cytoskeleton functions in diverse cellular processes, including cell motility, contractility, mitosis and cytokinesis, intracellular transport, endocytosis and secretion [1,2] In addition to these mechanical functions, actin has also been implicated in the regulation of gene transcription, through either cytoplasmic changes in cytoskeletal actin dynamics [3] or the assembly of transcriptional regulatory complexes [4] Cytoskeletal actin dynamics, i.e actin polymerization by which monomeric actin (globular actin or G-actin) is assembled into long actin polymers (filamentous actin or F-actin) and actin deploymerization by which F-actin is severed into G-actin, is key for these diverse functions The dynamic nature of the actin cytoskeleton is determined spatiotemporally by the actions of numerous actin-binding proteins (ABPs) The activity of different classes of ABP controls actin nucleation, bundling, filament capping, fragmentation and Abbreviations ABLIM, actin-binding LIM protein; ABP, actin-binding protein; ANF, atrial natriuretic factor; AR, androgen receptor; CARM1, coactivatorassociated arginine methyltransferase 1; CBP, CREB binding protein; DBD, DNA-binding domain; FHL, four and a half LIM domains; FLAP1, Fli-I LRR-associated protein 1; Fli-I, flightless-1; FLNa, filamin-A; FOXC1, forkhead box C1; GRIP1, glucocorticoid receptor-interacting protein 1; HAT, histone acetyltransferase; HDAC, histone deacetylase; HF, hydroxyflutamide; hhLIM, human heart LIM protein; hnRNPs, heterogeneous nuclear ribonucleoproteins; LBD, ligand-binding domain; LEF1 ⁄ TCF, lymphoid enhancer factor ⁄ T-cell factor; LRR, leucine rich repeat; MEF2, myocyte enhancer factor 2; MRTF, myocardin-related transcription factor; NLS, nuclear localization signals; NM1, nuclear myosin 1; PBX1, pre-B-cell leukemia transcription factor 1; PCAF, p300 ⁄ CREB binding protein-associated factor; PEBP2b, polyoma enhancer-binding protein; PIC, pre-initiation complex; Pol I, RNA polymerase I; Pol II, RNA polymerase II; Pol III, RNA polymerase III; RNP, ribonucleoprotein; SRF, serum response factor; STARS, striated muscle activator of Rho signaling; SV, supervillin; SWI ⁄ SNF, switch ⁄ sucrose nonfermentable complex FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS 2669 Actin and ABPs in transcription regulation B Zheng et al monomer availability Transcriptional regulation, mediated by cytoskeletal actin dynamics, can be attributed to modulation of the subcellular localization of transcriptional regulators by ABPs [5] In addition, some of the mechanisms by which actin affects transcription and its regulation depend on molecular interactions of actin with RNA polymerases and components of the transcription machinery in the nucleus The role of actin in transcription and its regulation Actin is both a major cytoskeletal component of all eukaryotic cells and also a constitutent of nuclear protein complexes Nuclear actin plays a role in many nuclear functions [6–8] First, nuclear actin is required for transcription by all three nuclear RNA polymerases Second, nuclear actin associates with small nuclear ribonucleoproteins (RNPs), which have a major role in mRNA processing [8,9], and is directly involved in the nuclear export of RNA and cellular proteins [10,11] Third, nuclear actin also forms complexes with certain heterogeneous nuclear ribonucleoproteins (hnRNPs) that bind to and accompany mRNA from the nucleus to the cytoplasm [12–14] Fourth, nuclear actin and actin-related proteins have been found in association with chromatin-remodeling and histone acetyl transferase complexes, suggesting a role for actin in chromatin remodeling [15] Recent investigations suggest that nuclear actin has a role in gene transcription associated with three main entities: components of the three RNA polymerases, ATP-dependent chromatin-remodeling complexes and RNP particles in the eukaryotic cell nucleus Nuclear actin is a constitutive component of all RNA polymerases Nuclear actin is required for the transcription of all three RNA polymerases Specifically, b-actin has been identified as a component of RNA polymerase II (Pol II) pre-initiation complexes (PICs) Injection of anti-actin Ig into the nuclei of salamander oocytes results in contraction of the lateral loops and the inhibition of transcription [8] Furthermore, Hofmann & de Lanerolle [16] found that actin is associated with actively transcribed genes and has an essential role in the activation of transcription In addition, actin is required for the initiation of transcription through participation in the formation of PICs [17] These conclusions are based on the following data: (a) b-actin participates directly in Pol II transcription, using only purified transcription factors [18,19]; (b) nascent RNA 2670 molecules are associated with actin in the nuclear matrix and antibodies to b-actin inhibit the synthesis of nascent transcripts and Pol II transcription [17,19]; (c) adding actin to a highly purified Pol II fraction stimulates transcription [19]; (d) actin colocalizes with transcription sites in early mouse embryos [4,17]; (e) actin is recruited to the promoter region of transcribing genes in vivo [19,20]; (f) antibodies to b-actin inhibit the production of a 15-nucleotide transcript that is a prerequisite for the commitment to elongation [19,21]; (g) actin is a component of pre-mRNP particles, and is incorporated into pre-mRNAs by binding to a specific subset of RNA-binding proteins [4,22]; and (h) actin is a component of PICs and depletion of actin prevents their formation [19,23] The above evidence suggests that there is a strong and specific interaction between actin and Pol II, and actin participates in Pol II transcription What then is the function of actin in Pol II transcription? From the above data, we conclude that: (a) based on chromatin immunoprecipitation assays results, which show that actin is recruited to genes poised to begin transcribing, it is known that actin is involved in recruiting Pol II to the PIC [19]; (b) decreased actin levels resulting from antiactin Ig inhibit PIC formation by preventing the binding of TBP to the TATA box, indicating that PIC formation is required for the association of actin with promoter DNA [19]; (c) antibodies to b-actin prevent PIC formation, suggesting that actin acts as a bridge between the polymerase and other constituents of the PIC [24]; and (d) actin and nuclear myosin (NM1), an isoform of myosin 1, are involved in transcription elongation [6,25,26] Together, these data suggest that actin is involved in multiple stages of the transcription process b-Actin also has an important role in RNA polymerase III (Pol III) transcription [27] First, b-actin is tightly associated with Pol III via direct protein–protein interactions with one or more of the RPC3, RPABC2 and RPABC3 subunits, and constitutes part of the active Pol III [27] Photochemical cross-linking experiments, performed using a transcription initiation complex, indicated that actin makes complex contact with DNA [28] Second, chromatin immunoprecipitation assays identified that b-actin is located at the promoter sequences of an actively transcribed U6 gene in vivo, which suggests that it participates in the transcription of Pol III [27,29,30] Upon treatment with methane methylsulfonate, a drug that represses Pol III transcription, the U6 initiation complex and b-actin are largely dissociated from promoter sequences [27,29,31] Notably, there is a much larger decrease in the association between b-actin and the U6 promoter FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS B Zheng et al region when compared with the dissociation of Pol III, which suggests that b-actin dissociates from the Pol III complex Third, many experiments have shown that b-actin is required for Pol III transcription [27,29,32] The monomeric form of actin is required for Pol III transcription, suggesting that b-actin is essential for basal RNA polymerase transcription Actin and NM1 interact with different components of the RNA polymerase I (Pol I) machinery, and together serve as a nucleolar motor involved in the transcription of ribosomal RNA genes [26,33] Recent studies have revealed that actin is associated with rDNA genes, and microinjection of anti-actin Ig into the nuclei of HeLa cells inhibits pre-rRNA synthesis in vivo [25,34] The interaction of NM1 with actin in the initiation complex may trigger a conformational change that favors the transition of Pol I from the initiation phase to the elongation phase [25,33] NM1 mutants that lack ATPase activity or actin binding are not capable of associating with Pol I [17], and their association with rDNA is greatly impaired Moreover, the association of actin and NM1 with Pol I is abolished in the presence of ATP and is stabilized by ADP, further suggesting that nuclear actomyosin complexes act as a molecular motor that facilitates transcription [17] NM1 binds the DNA backbone via its positively charged tail domain, whereas the head interacts with actin bound to RNA polymerase [4] It has been suggested that by anchoring NM1 to DNA, and actin to RNA polymerase, an auxiliary motor is generated that works in concert with nuclear RNA polymerases to drive transcription [23] This suggests that the cooperative action of actin and myosin in the nucleus is required for Pol I transcription and reveals an actomyosin-based mechanism in transcription Actin serves as components of chromatin-remodeling complexes Actin is essential for the function of chromatin-remodeling complexes in transcriptional activation Nuclear actin is an ATPase that cycles between monomeric (G-actin or b-actin) and polymerized (F-actin) states [4] Eukaryotic cells have several ATP-dependent chromatin-remodeling complexes, depending on the ATPase in the complex, as follows: switch ⁄ sucrose nonfermentable (SWI ⁄ SNF) complexes, imitation of SWI-containing complexes, Mi-2 complexes, histone acetyltransferase complexes, such as the Nu4A and TIP60 complexes, and INO80 complexes b-Actin is an integral component of chromatin-remodeling complexes, such as the BAF, BAP and INO80 complexes, as well as Nu4A and TIP60 complexes [24,27,29,35–38] Actin and ABPs in transcription regulation It is generally accepted that chromatin-remodeling complexes contain actin, actin-related proteins and ⁄ or ABPs Nuclear actin-related proteins (ARP5–9) are associated with actin in chromatin-remodeling complexes of the SWI ⁄ SNF family, such as those containing the ATPase subunits INO80 or SWR1 [15,24,39] In the SWI ⁄ SNF-like BAF complex, b-actin binds directly to the BRG1 ATPase subunit of BAF and stimulates BRG1 ATPase activity, and this interaction is necessary for binding of the BAF complex to chromatin [27,29,40] Actin binding to BRG1 is required for stable association of the complex and provides a link between the chromatin-remodeling complex and the nuclear matrix [5,41] In the INO80 complex, actin is required for efficient DNA binding, ATPase activity and nucleosome mobilization, as INO80 complexes lacking actin, as well as the actin-related proteins, ARP4 and ARP8, are deficient for these activities [15] BAF53 and b-actin have also been identified as subunits of the human TIP60 histone acetyltransferase (HAT) complex, which is involved in DNA repair and apoptosis, and BAF53 is found in a distinct HAT complex involved in c-myc activation, whereas Act3 ⁄ ARP4 and actin are components of the yeast Nu4A HAT complex [38,42] In the yeast Nu4A HAT complex, actin and Act3 ⁄ ARP4 are essential for the structural integity and activity of the complex [38] The presence of actin in chromatinremodeling complexes suggests that there is a functional link between actin and regulation of the chromatin structure, and a major function of actin is to act as an allosteric regulator in the remodeling of some macromolecular assemblies, such as chromatin-remodeling factors or transcription complexes Actin serves as a component of RNP The hnRNP U, a component of pre-mRNP particles, has been shown to interact directly with actin through a specific and conserved actin-binding site located in the hnRNP U C-terminus and associate with the phosphorylated C-terminal domain of Pol II [43] Injection of a peptide acting as a competitive inhibitor of protein–protein contact involving actin and the hnRNP protein, HRP36, into the salivary glands of Chironomus tentans disrupts global Pol II transcription as measured by bromo-UTP incorporation; an effect that is caused, at least in part, by a decrease in elongation measured by run-on assays [22] A recent study has shown that actin binds directly to C tentans hnRNP, HRP65-2, which is a molecular platform for recruitment of the HAT histone H3-specific acetyltransferase p2D10 on active genes Both actin and the pre-mRNP protein, HRP65, are complexed in situ with p2D10, FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS 2671 Actin and ABPs in transcription regulation B Zheng et al and disruption of the actin–HRP65 interaction releases p2D10 from Pol II-transcribing genes, coincident with reduced H3 acetylation and diminished transcription [6] HRP65-2 binds directly to p2D10, and the interaction between actin and HRP65-2 is required for p2D10 to associate with the transcribed chromatin [6] Moreover, the association of p2D10, actin and HRP65-2 with chromatin is sensitive to ribonuclease digestion, which indicates that these proteins are tethered to the transcribed genes by binding to the nascent transcript These findings support the idea of a link between nuclear actin, chromatin remodeling and Pol II transcription [43,44] Obrdlik et al [13,45] identified that the HAT, p300 ⁄ CREB binding protein (CBP)associated factor (PCAF), associates with actin and hnRNP U Moreover, it has been shown that actin, hnRNP U and PCAF associate with the Ser2 ⁄ 5and Ser2-phosphorylated Pol II C-terminal domain hnRNP U and PCAF are present at the promoter and coding regions of constitutively expressed Pol II genes and are associated with RNP complexes [13] In summary, these finding suggest that actin, HRP65-2 and HAT (p2D10 or PCAF) are assembled into nascent pre-mRNPs during transcription Based on the evidence, it may be proposed that the actin–HRP65-2– HAT complex is part of the nascent pre-mRNP, and can travel along the transcribed gene, allowing HAT to acetylate histones According to this proposal, the actin–HRP65-2–HAT complex maintains the chromatin in a transcription-competent conformation This model is supported by the observation that H3 acetylation is reduced and transcription is inhibited when the interaction between actin and HRP65-2 is disrupted [22] In addition, actin-mediated Pol II transcriptional control may be sensitive to the different polymerization states of actin [17] Transcriptionally competent actin may be present in a monomeric or oligomeric form which is different from the canonical actin filaments The polymerization states of actin involved in the initiation or elongation phases are different (Fig 1) [43] Roles of ABPs in the regulation of muscle-specific gene expression The cytoplasmic dynamics of the actin cytoskeleton have been shown to regulate the subcellular localization of some transcription factors, such as the myocardin-related transcription factors MRTF-A (also referred to as MAL, MKL1 and BSAC) and MRTF-B (also referred to as MKL2 or MAL16) [46,47], the developmentally regulated PREP2 homeoprotein, and the transcriptional repressor Yin-Yang [48,49] Because actin dynamics are regulated by a number of ABPs, ABPs may play a critical role in the regulation of transcription and gene expression [50] Studies have established that some ABPs induce the formation of actin filaments by their ability to nucleate actin filament polymerization; other ABPs promote filament breakdown by a mechanism referred to as severing Still other ABPs cross-link or bundle actin filaments or prevent filament formation by their so-called sequestering activity Among the notable transcription factors controlled by ABPs are MRTFs, which associate with serum response factor (SRF) and stimulate SRFdependent transcription [46,51,52] In addition, actin dynamics are regulated by several signal transduction cascades that converge on ABPs [53] Pol II Activator Pol II TF TF TF CTD CTD Actin hnRNP U Actin P ? TBP Ac Ac P Actin PCAF or P2D10 Actin polymerization HRP65-2 hnRNP U mRNA processing P Actin Pre-mRNA Fig Model for actin–hnRNP U-mediated control of pol II transcription elongation Actin may modulate several steps in Pol II transcription initiation and elongation, either as a monomer or as a polymer Actin may modulate transcription as a monomeric component of transcription preinitiation, chromatin-remodeling and hnRNP complexes During transcription elongation, actin may be recruited to the elongating transcription machinery via the hyperphosphorylated C-terminal domain and then to the nascent RNP, where actin in complex with the hnRNP U can facilitate recruitment of PCAF or P2D10 to the active gene Formation of actin filaments in the proximity of the Pol II C-terminal domain may help establish a network of interactions between the various factors necessary for transcription elongation and pre-mRNA processing 2672 FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS B Zheng et al MRTF-A associates with G-actin, is predominantly localized in the cytoplasm of NIH 3T3 cells in the absence of serum and accumulates in the nucleus in response to serum stimulation MRTF-B also undergoes nuclear translocation in response to serum stimulation, although it is less responsive than MRTF-A [54] Upon activation of RhoA, actin becomes polymerized and releases MRTF-A, which in turn translocates to the nucleus to associate with SRF [46] Striated muscle activator of Rho signaling (STARS) is a muscle-specific ABP capable of stimulating SRFdependent transcription via a mechanism involving RhoA activation and actin polymerization [55] Recently, MRTF-A and -B were shown to serve as a link between STARS and SRF In NIH 3T3 cells cotransfected with expression plasmids encoding MRTFs and STARS, the MRTFs are translocated to the nucleus in the absence of serum The nuclear localization of myocardin is unchanged in the absence or presence of STARS [54] Thus, STARS may substitute for serum stimulation and promote the nuclear translocation of MRTFs with the consequent activation of SRF-dependent transcription Kuwahara et al [54] found that coexpression of STARS with a dominantnegative myocardin mutant, which can inhibit the transcriptional activities of myocardin and MRTF-A and -B, can completely block the ability of STARS to induce SRF-dependent transcription in NIH 3T3, COS1 and 293T cells However, STARS does not alter the level of expression of MRTFs These observations suggest that STARS stimulates SRF-dependent transcription solely by promoting the nuclear translocation of MRTF-A and -B The STARS protein contains 375 amino acids, with the conserved ABD contained within the C-terminal 142 residues [55] The STARS C-terminal deletion mutant, N233, which cannot bind actin or activate SRF, fails to induce the nuclear accumulation of MRTF-A and -B By contrast, the C-terminal 142 amino acids of STARS, which bind actin and stimulate SRF, induce the nuclear accumulation of MRTFs as efficiently as full-length STARS STARS N233 fails to enhance MRTF-dependent activation of SRF-dependent reporters, whereas STARS C142 synergistically enhances MRTF-mediated transcription to the same level as full-length STARS [55] These results demonstrate that the ABD of STARS is both necessary and sufficient for the nuclear accumulation and transcriptional activation of MRTFs by STARS The activity of STARS involves actin dynamics Treatment of NIH 3T3 cells with latrunculin B, which sequesters actin monomers and prevents Rho-dependent nuclear accumulation of MRTF-A and SRF Actin and ABPs in transcription regulation activation [46], blocks the nuclear accumulation of MRTF-A and -B in the presence of STARS Conversely, cytochalasin D, which dimerizes actin, but prevents actin polymerization and activates SRF, strongly induces the nuclear translocation of MRTFs, even in the absence of STARS [54] Consistent with these effects on MRTF nuclear import, latrunculin B significantly blocks the stimulatory effect of STARS on MRTF-dependent transcription, and cytochalasin D enhances the activity of MRTFs alone These results indicate that actin dynamics are involved in the STARS-induced nuclear accumulation of MRTFs and transcriptional activation of SRF via MRTFs MRTF-A was recently reported to interact directly with G-actin [56] Unpolymerized G-actin controls MRTF activity [46], and STARS induces actin polymerization [55] Kuwahara et al [54] demonstrated that expression of wild-type actin, which increases the amount of G-actin, but does not alter the F-actin ⁄ G-actin ratio, reduced the ability of STARS to activate MRTF-dependent transcription Wild-type actin did not significantly alter the activity of MRTF in the absence of STARS The actin mutant that favors F-actin formation and increases the F-actin ⁄ G-actin ratio [56] stimulates MRTF activity, even in the absence of STARS, and abolishes further activation of MRTFs by STARS By contrast, the actin mutant that is unable to polymerize and decreases the F-actin ⁄ G-actin ratio inhibits MRTF activity and also reduces the ability of STARS to enhance MRTF activity These results suggest that STARS stimulates MRTF activity by inducing the dissociation of MRTFs from actin via depletion of the G-actin pool The N-terminal regions of MRTFs contain three RPEL motifs which have been shown to sequester MRTFs in the cytoplasm by association with actin [46,56] Consistent with STARS promoting the nuclear import of MRTFs by displacing them from monomeric G-actin, the RPEL motifs are required for the effects of STARS on MRTFs MRTFs are cytoplasmic, accumulating in the nucleus upon activation of Rho GTPase signaling, which alters interactions between G-actin and the RPEL domain Guettler et al [57] showed that the RPEL domain of MRTF-A binds actin more strongly than the RPEL domain of myocardin, and that the RPEL motif itself is an actin-binding element RPEL1 and RPEL2 of myocardin bind actin weakly compared with MRTF-A, whereas RPEL3 is of comparable and low affinity in the two proteins Actin binding by all three motifs is required for MRTF-A regulation The differing behaviors of MRTF-A and myocardin are specified by the RPEL1– RPEL2 unit, whereas RPEL3 can be exchanged FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS 2673 Actin and ABPs in transcription regulation B Zheng et al between them It has been proposed that differential actin occupancy of multiple RPEL motifs regulates nucleocytoplasmic transport and MRTF-A activity Because myocardin is insensitive to the effects of STARS, its target genes are expected to be highly active, irrespective of the polymerization state of actin However, STARS would be expected to further augment the expression of these genes via its actions on MRTF-A and -B, which are also expressed in cardiac muscle and which form heterodimers with myocardin In a yeast two-hybrid screen of a skeletal muscle cDNA library using STARS as bait, Barrientos et al [58] identified two novel members of the actin-binding LIM protein (ABLIM) family, ABLIM-2 and -3, as STARS-interacting proteins These novel proteins contain four LIM domains and a C-terminal villin headpiece domain, which mediates actin-binding in several proteins, such as villin and dematin [59] Both ABLIM-2 and -3 show high homology with ABLIM-1 ABLIM-1 was originally found in the human retina, as well as in the sarcomeres of murine cardiac tissue, and was postulated to regulate actin-dependent signaling [60] Similarly, ABLIM-2 and -3 are expressed in a tissue-specific pattern ABLIM-2 is highly expressed in skeletal muscle and at lower levels in brain, spleen and kidney No significant expression has been detected in the heart In contrast to ABLIM-2, ABLIM-3 is predominantly expressed in human heart and brain, whereas the murine ABLIM-3 homolog displays a somewhat broader tissue distribution that also includes lung and liver [58] Both ABLIM-2 and -3 strongly bind F-actin and colocalize with actin stress fibers The interaction of STARS with ABLIM-2 and -3 was confirmed by coimmunoprecipitation and further supported by the colocalization of STARS and ABLIM-2, as detected by immunofluorescence [58] The complementary expression patterns of ABLIM-2 and -3 in striated muscle imply that, in vivo, STARS interacts with ABLIM-2 in skeletal muscle and ABLIM-3 in cardiac muscle Consistent with the notion that STARS activates SRFdependent transcription via stabilization of the actin cytoskeleton [54], both ABLIM-2 and -3 modulate STARS-dependent activation of a luciferase reporter construct controlled by the SM22 promoter, which contains two essential SRF-binding sites and is highly sensitive to STARS activity [58] The data suggest that ABLIM-2 and -3 stimulate STARS activity ABLIM-2 and -3 enhance STARS-dependent SRF-transcription in COS cells in a dose-dependent manner [58], suggesting that STARS and ABLIMs both physically interact and functionally synergize to deliver activating signals to SRF The data imply that, in striated muscle, 2674 STARS plays a critical role in the MRTF-A nuclear translocation process; STARS promotes the nuclear translocation of MRTFs, and thereby SRF-dependent transcription (Fig 2) STARS activation of SRF-dependent transcription is mediated, in part, by a Rho-dependent mechanism, because the Rho inhibitor C3 transferase reduces SRF activation by STARS The ability of the Rho kinase inhibitor, Y-27632, to diminish SRF activation by STARS also suggests that Rho kinase is a downstream effector of STARS [55] The Rho family of GTPases, including the best characterized members, Rho, Rac and Cdc42, serve as molecular switches in the regulation of a wide variety of signal transduction pathways [61,62], in particular, actin polymerization and stress fiber formation [63] RhoA signaling has been shown to induce the nuclear import of MRTF-A in smooth muscle cells, thereby triggering smooth muscle gene activation [64] It is well-known that actin dynamics and Rho signaling are involved in STARS-induced nuclear translocation and transcriptional activation of MRTFs, and Rho activity is crucial for actin dynamics Kuwahara et al [54] showed that the dominant-negative RhoA mutant inhibits the nuclear accumulation of MRTFs and the stimulatory effect of STARS on the transcriptional activity of MRTFs Although STARS requires Rho activity to induce actin treadmilling and MRTF nuclear translocation, and the inhibition of Rho activity blocks STARS activity, assays of RhoA activity in STARS-transfected cells did not differ from those in untransfected cells Thus, Fig Model of the involvement of STARS and ABLIM in actin dynamics and SRF-dependent transcription FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS B Zheng et al Actin and ABPs in transcription regulation STARS does not appear to function as an upstream activator of Rho, but requires Rho–actin signaling and changes in actin dynamics to evoke its stimulatory effects on MRTFs and SRF activity Taken together, the small GTPase acts downstream of STARS, and it seems possible that ABLIM integrates signals from the small GTPases, Rac and RhoA (via STARS) toward the actin cytoskeleton Roles of ABPs in the regulation of nuclear receptor Nuclear receptors regulated by ABPs include the glucocorticoid receptor, estrogen receptor, androgen receptor (AR), thyroid receptor and peroxisome proliferator-activated receptor-c Among these, the AR is the most widely studied and well-characterized The AR is a ligand-activated transcription factor that controls the expression of genes involved in functions such as cell proliferation, cell growth, differentiation and cell death [65,66] The AR contains an N-terminal domain harboring activation function 1, a central DNA-binding domain (DBD) and a C-terminal ligandbinding domain (LBD) containing activation function [67–70] Upon binding androgens, the AR LBD undergoes conformational changes leading to dissociation from chaperones and translocation to the nucleus [71–74] AR binding to DNA facilitates the recruitment of general transcriptional machinery and ancillary factors that result in the activation or repression of specific genes in targeted cells and tissues [75] In the last decade, an increasing number of proteins have been proposed to possess AR coactivating or corepressing characteristics [76,77] Cofactors facilitate AR transcription function by histone modifications, chromatin remodeling and regulation of the AR N-terminal domain, and the LBD interaction (N ⁄ C interaction) [78–82] All available data suggest that no single AR-binding protein completely defines the multiple functions of the AR in controlling cellular growth and differentiation in normal and malignant cells [75] Alternatively, AR pleiotropic activities are probably mediated through its binding to specific functional protein complexes to carry out its broad biological functions in mammalian cells More than 200 nuclear receptor coregulators have been identified since the first nuclear receptor coactivator, SRC-1, was isolated in 1995 [83] Among the nuclear receptor coregulators, ABPs and actin monomers bind to the AR, indicating that they also play an important role in AR-mediated transcription (Fig 3) [5,84] For example, supervillin, a nuclear ⁄ cytoplasmic F-actin-bundling protein, is able to interact with the AR N-terminal domain and DBD– LBD This association is enhanced in the presence of androgens [85] In recent years, ABPs have been shown to elicit increased activity in regulating AR than was previously thought (Table 1) Filamin, originally identified as a protein that facilitates nuclear transport of the AR, interacts with the AR DBD–LBD in a ligand-independent manner [77,86,87] The absence of filamin hampers androgeninduced AR transactivation In the absence of filamin, the receptor–Hsp90 (Hsp90 is a chaperone protein that plays a key role in the conformational change and transcriptional activity of the AR) complex may remain inactive, anchored to the actin filaments, even in the presence of steroid and an available nuclear localization sequence on the receptor [87] Filamin may act as a mediator between the receptor and the Hsp90, and control the release of activated receptor after ligand binding in AR cytoplasmic trafficking [87,88] Filamin-A (FLNa) interferes with AR interdomain interactions and competes with the coactivator transcriptional intermediary factor (TIF2) to specifically downregulate AR function [86] When cleaved at the protease-cleavage site between repeats 15 and 16, AR N/C interaction Coactivator competition ABPs HDAC chromatin condensation Actin Coactivators HAT AR AR ABPs AR AR Pol II ARE AR HSP AR nuclear translocation Actin ABPs Fig Regulation of androgen receptor gene transcription by actin-binding proteins FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS 2675 Actin and ABPs in transcription regulation B Zheng et al Table Role of nuclear actin-binding proteins interacting with the androgen receptor AR, androgen receptor; LBD, ligand-binding domain Actin-binding protein Targeting sequence Gelsolin Direct or indirect association with the AR Region LBD Classes Role in the cytoplasm AR effect Mechanism ()) Actin filament severing and capping protein Coactivator Promotes AR activity in a ligand-enhanced manner Direct Flightless I NLS Actinremodeling proteins Involved in gel-to-sol transformations; severs and caps polymeric actin filaments; acts in the actin-scavenging system; inhibits actin polymerization Possess F-actin-serving activity Coactivator Does not enhance the activity of ARs alone, but requires the presence of a p160 coactivator Direct a-actinin-2 ()) Bundling proteins Coactivator Supervillin NLS F-actin- and membraneassociated scaffolding protein Filamin NLS? Cross-linking proteins Filamin A NLS? Cross-linking proteins Transgelin ()) Cross-linking proteins Functions as scaffolds for signaling intermediates that stimulate actin elongation; binding partners for ICAM-1 Regulates cell-substrate adhesion; organization of muscle co-stameres; stimulus-mediated contractility of smooth muscle and myogenic differentiation Cytoplasmic transport; membrane integrity; cellular adhesion Cross-links actin filaments; recruits F-actin into extended networks Organizes actin filaments into dense meshworks full-length FLNa releases FLNa(16–24) [86–90] This naturally occurring C-terminal 100 kDa fragment of filamin, interacting with the motor protein dynein, may exert its inhibitory effect by interfering with interactions between the N- and C-terminal domains, and the coactivator functions of the AR [86,91] Full-length FLNa is bound to the actin cytoskeleton on the cell surface and perinuclear areas of the cell via its N-terminal ABD In the absence of ligand, AR is localized predominantly in the cytoplasm, and its hinge domain and the LBD are tethered to the C-terminal end of FLNa [86] FLNa(16–24) colocalizes with liganded AR to the nucleus In the nucleus, FLNa(16–24) disrupts interactions between the N- and C-termini of the AR, and interferes with the binding of the coactivator TIF2 2676 Indirect Coactivator Increases interaction frequency with the AR Direct N- and C-Terminal Coactivator AR cytoplasmic trafficking Direct Hinge Corepressor Inhibits N ⁄ C, suppresses TIF2 activation Through ARA 54 Direct Hinge Indirect LBD Corepressor [86,91] There is evidence that interaction between the FXXLF (X = any amino acid) motif of the TAD and the LBD reduces coactivator recruitment and binding of the LXXLL motif of TIF2 [92] Alternatively, FLNa(16–24) may also directly recruit transcriptional repressors to the target promoter or possess intrinsic histone deacetylase activity to inhibit transcription initiation [86] In addition, the recent report of Rhoregulated PAK6 as an AR hinge-interacting kinase [93] suggests that the FLNa(16–24)–AR hinge complex may serve as an integrator for the many cytoskeletal signaling cascades that converge on the AR Supervillin (SV) was initially identified from blood cells as an ABP and was found to be expressed in skeletal muscles and several cancer cell lines [94] FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS B Zheng et al SV is localized to the plasma membrane at sites of intracellular contact The nuclear localization signal is located in the middle of this protein [95] At low density, SV shows a punctate distribution localized to the cytoplasm and nucleus, whereas at high density, SV is localized almost exclusively to the plasma membrane SV has been identified as an AR-interacting protein, which can interact with both N-terminal activation function-1 and C-terminal activation function-2 of the AR and plays a role in AR dimerization [85] The functional coregulator domain of SV is located at amino acids 831–1281 of bovine origin, which has putative actin-binding sites and nuclear localization signals (NLS) [96] Ting et al [96] showed that SV (amino acids 831–1281) has a better enhancing effect on AR transactivation than full-length SV and SV (amino acids 1010–1792) It is possible that by remaining within the nucleus, SV may increase the interaction frequency with the AR, resulting in a change in AR conformation to an activated form to facilitate binding of the androgen response element located in the target genes SV is relatively weak in promoting non-androgenic steroid-mediated AR transactivation, but is capable of coordinating with other coregulators, including ARA55 and ARA70, to enhance AR transactivation [96,97] These results suggest that the final AR activity may involve balancing and coordinating multiple coregulators in any given cell In addition, previous experiments reported that actin and SV potentiate each other in promoting AR activity [96] Because several putative actin-binding sites and functional NLS of SV are important for the AR transactivation function, and the minimal functional fragment of SV, which only contains one actin-binding site, is located in the nucleus, recruiting actin into the chromatin-remodeling complex is a potential mechanism of co-regulator activity [96] The actin chelator, latrunculin B, which attenuates the coregulator function of both full-length SV and the minimal functional fragment, also identifies this potential mechanism Furthermore, Rac signaling stimulates membrane ruffling that further attenuates the coregulator activity of SV There are two possible explanations for this: (a) the accumulation of SV in the membrane prevents it from associating with AR; and (b) a decrease in the amount of actin monomer affects SV coregulator activity, which requires actin monomers [96] However, SV has no effect on the cytoplasmic–nuclear translocation of the AR, and does not affect the half-life of the AR [85] Gelsolin is a multifunctional ABP, implicated in cell signaling, cell motility, apoptosis and carcinogenesis [98,99] Gelsolin regulates actin polymerization and depolymerization by sequestering actin monomers, and Actin and ABPs in transcription regulation can sever and cap actin filaments [1] Nishimura et al [100] identified gelsolin as an AR-interacting protein that can enhance its transactivation in prostate cancer cells Because gelsolin lacks a nuclear localization signal, it may be cotranslocated into the nucleus upon binding to other proteins [100] Like filamin, gelsolin is able to interact with AR at the time of its nuclear localization to facilitate the nuclear translocation of AR [87] Increased expression of gelsolin can enhance AR activity under hydroxyflutamide (HF) with low levels of androgen treatment to maintain AR-mediated growth and theh survival of tumor cells Gelsolin itself interacts with AR LBD via FXXFF and FXXMF motifs and enhances its activity in the presence of androgen The interaction between the N- and C-termini of the AR does not affect gelsolin FXXFF binding to AR LBD, indicating that the gelsolin FXXFF motif has a higher affinity for AR LBD [71] Two peptides, D1 (amino acids 551–600) and H1–2 (amino acids 665–695) located within AR DBD and LBD, respectively, can block gelsolin-enhanced AR activity [100] Altogether, gelsolin interacts with the AR during nuclear translocation and enhances ligand-dependent AR activity Transgelin, also termed SM22a, was first isolated from chicken gizzard as a transformation- and shape change-sensitive ABP [101] Recently, Yang et al [102] characterized transgelin as a potential suppressor of prostate cancer via inhibition of ARA54-enhanced AR transactivation ARA54, a RING finger protein, interacts with AR and enhances its transcriptional activity in a ligand-inducible manner Transgelin does not interact directly with the AR, but exerts its effects through recruitment to ARA54 ARA54 can interact with transgelin both in vitro and in vivo in an androgen-independent manner [102] The data suggest that transgelin might need the specific interaction with ARA54 to suppress AR transactivation By contrast, transgelin shows little interaction with the AR, ARA70, ARA55, SRC-1, supervillin, gelsolin and CREB binding protein (CBP) Silencing of endogenous ARA54 via its siRNA can abolish the suppressive effect of transgelin on AR function [102] This suggests that transgelin may be able to suppress ARA54-enhanced AR transactivation by interrupting the interaction between the AR and ARA54, as well as ARA54 homodimerization, resulting in enhanced cytoplasmic retention and impaired nuclear translocation of ARA54 and the AR Flightless-1 (Fli-I) is an ABP that can be either associated with the cytoskeleton or found in the nucleus, but its exact physiologic functions have not been elucidated [103] Fli-I can associate directly with the AR and function in cooperation with specific combinations of FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS 2677 Actin and ABPs in transcription regulation B Zheng et al other AR coactivators to enhance the ability of the AR to activate the transcription of AR-regulated genes [77] Because Fli-I does not enhance AR activity by itself, but requires the presence of a p160 coactivator, binding of Fli-I to the AR is apparently insufficient for Fli-I coactivator function [104] The contacts between Fli-I and multiple components in the transcription complex (AR, glucocorticoid receptor-interacting protein 1, GRIP1, p160 and coactivator-associated arginine methyltransferase 1, CARM1) may result in more efficient recruitment of Fli-I to the promoter, a more stable coactivator complex or a more highly functional conformation of the coactivator complex Fli-I is a secondary coactivator in AR transcription activation [104] a-Actinin-2 is a major structural component of sarcomeric Z-lines in skeletal muscle, where they function to anchor actin-containing thin filaments in a constitutive manner [105] a-Actinin-2 enhances the transactivation activity of SRC-2 and serves as a primary coactivator for the AR, acting in synergy with SRC-2 to increase AR transactivation function [106] Huang et al [106] indicated that wild-type a-actinin-2 (containing a LXXLL motif) and mutant a-actinin-2 (mutation of the LXXLL motif to LXXAA) both bind to the AR, but the mutant form shows much weaker binding than wild-type a-actinin-2 That is to say, the LXXLL motif in a-actinin-2 has a major role in the interaction with the AR However, the LXXLL motif of a-actinin-2 is dispensable for its primary coactivator role in NR functions, because two truncated a-actinin-2 fragments (encoding 281–700 and 701–894), lacking the LXXLL motif, and mutant a-actinin-2 (LXXAA) retain the primary and secondary coactivator functions of wild-type a-actinin-2 In addition, a-actinin-2 not only serves as a primary coactivator in the AR, but also interacts synergistically with GRIP1 and enhances GRIP1-induced AR coactivator functions in the presence of cognate ligands [106] Furthermore, a-actinin-4 also binds to the AR and exhibits coregulating properties a-Actinin-4 may target the AR for degradation and ⁄ or antagonize AR synthesis upon the addition of androgen In addition, a-actinin-4 negatively regulates AR-mediated transcription [75] transcription factors or the assembly of transcriptional regulatory complexes [107] ABPs can recruit multiple components to transcription complexes through different types of interactions Fli-I binds both actin and the actin-like BAF53 (BAF complex 53 kDa subunit, BRG1-associated factor), as well as p160 co-activator [104,108] Fli-I can help to secure the association of an SWI ⁄ SNF complex to a p160 coactivator complex Fli-I thus helps to coordinate the complementary ATP-dependent nucleosomeremodeling activity of the SWI ⁄ SNF complex with the histone acetylating (e.g from CBP and p300) and methylating (e.g from CARM1 and protein arginine methyltransferase 1) activities of the p160 coactivator complex [109] In addition, Fli-I and Fli-I LRR-associated protein (FLAP1) have an important role in regulating transcriptional activation by b-catenin and lymphoid enhancer factor ⁄ T-cell factor (LEF1 ⁄ TCF) FLAP1 is a key activator, cooperating synergistically with p300 to enhance LEF1 ⁄ TCF-mediated transcription by b-catenin Fli-I negatively regulates the synergy of FLAP1 and p300 [103] Lee & Stallcup [103] found that Fli-I does not bind well to the p300 KIX domain and does not appear to inhibit FLAP1–p300 binding, suggesting that Fli-I does not interfere with the binding of FLAP1 to p300 Fli-I may exert its negative influence by inhibiting the activity of FLAP1 and other essential factors that bind to Fli-I (Fig 4) It is also possible that Fli-I may recruit negative regulators, such as histone deacetylases (HDACs), CtBP, Groucho and Chibby, to the b-catenin ⁄ LEF1 ⁄ TCF transcription complex Both the leucine-rich repeat (LRR) and gelsolin-like domains of Fli-I are required for the negative Roles of ABPs in the regulation of transcription complexes More and more experiments have identified that proteins traditionally thought to be strictly cytoplasmic structural factors can influence gene regulation ABPs transduced the changes in cell structure that occur during morphogenesis to the nucleus, resulting in changes in gene expression via either the nuclear shuttling of 2678 Fig Model of Fil-I participation in transcription regulation Fli-I protein can bind to components of the p160 coactivator complex (p160 and CARM1), which has histone acetylating (CBP ⁄ p300) and methylating (CARM1) activities Fli-I can also bind to actin and the actin-like protein BAF53, both of which are components of the ATP-dependent nucleosome-remodeling complex SWI ⁄ SNF FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS B Zheng et al regulation of b-catenin function Increased nuclear levels of Fli-I presumably favor NR-mediated transcription, whereas lowered nuclear levels of Fli-I or increased levels of FLAP1 probably result in the release of FLAP1 and activate b-catenin ⁄ LEF1 ⁄ TCFmediated transcription through the synergy of FLAP1 and p300 Because Fli-I acts positively on NR-mediated transcription and negatively on b-catenin ⁄ LEF1 ⁄ TCF-mediated function, Fli-I may help to determine the balance between NR and b-catenin ⁄ LEF1 ⁄ TCF activity [104] FLNa interacts with transcription factor forkhead box C1 (FOXC1) and serves as a transcriptional barrier for FOXC1 activity [107] The proposed mechanism for transcriptional regulatory activity by FLNa is as follows (a) In the cytoplasm, FLNa cross-links with actin filaments to regulate actin cytoskeletal integrity Full-length FLNa can be localized to the nucleus (b) Nuclear import of transcriptional regulatory molecules, such as pre-B-cell leukemia transcription factor (PBX1), is regulated by FLNa Such regulation may be achieved by the association of FLNa with protein kinases That is to say, efficient nuclear localization of PBX1 and the formation of a transcriptionally inactive FOXC1–PBX1 complex required FLNa (c) In response to cell stimuli and cytoskeletal reorganization, FLNa expression and the levels of the nuclear FLNa pool increase In the nucleus, FLNa acts as a scaffold for the assembly of FOXC1 and PBX1 transcriptional inhibitory complexes Interaction of FOXC1 and FLNa partitions FOXC1 to HP1a-rich condensed heterochromatin in the nucleus and promotes an inhibitory interaction between FOXC1 and PBX1, reducing FOXC1 transactivity Furthermore, FOXC1–PBX1 complexes are unable to recruit coactivator complexes and are targeted to transcriptionally inactive, HP1arich heterochromatin regions of the nucleus [107,110] That is to say, FLNa can promote the active repression of FOXC1 activity via an association with inhibitory proteins, rather than simply prevent FOXC1 activation [107] FLNa also interacts with polyoma enhancer-binding protein (PEBP2b) FLNa retains PEBP2b in the cytoplasm, thereby hindering its engagement as a Runx1 partner However, PEBP2b is translocated into the nuclei in cells lacking FLNa, which enhances the transcriptional activity of PEBP2 ⁄ CBF The interaction with FLNa is mediated by a region within PEBP2b that includes amino acid residues 68–93 Deletion of this region enables PEBP2b to translocate to the nucleus [111,112] a-Actinin-4 is capable of interacting with class II HDACs and other transcription factors, and potentiates transcription activity by myocyte enhancer Actin and ABPs in transcription regulation factor (MEF2) [113] First, transient transfection data indicate that a-actinin-4 potentiates transcriptional activity by MEF2 Second, overexpression of a-actinin-4 decreases the interaction of MEF2A and HDAC7 Third, knockdown of a-actinin-4 decreases expression of TAF55 Fourth, MEF2C, a-actinin-4 and HDAC7 associate with the TAF55 promoter Furthermore, HDAC7 binds to amino acids 1–86 of MEF2A, suggesting that MEF2 cannot bind HDAC7 and a-actinin-4 simultaneously Thus, a possible competition model is that MEF2 may directly recruit a-actinin-4 to displace HDAC7 from MEF2 Alternatively, HDAC7 may recruit a-actinin in response to stimuli followed by association of a-actinin-4 with MEF2 and activation of transcription [77,113] Four and a half LIM domain (FHL) family members also belong to the family of ABPs and are directly involved in the differentiation of muscle cells The best-characterized member of this family is FHL2 ⁄ DRAL FHL2 has potential transcriptional activity and participates in a number of transcription regulations [114] Labalette et al [115] identified that FHL2 cooperates with CBP ⁄ p300 and activates b-catenin ⁄ TCF target gene cyclin D1 FHL2 also interacts with myocardin and enhances myocardin and myocardin-related transcription factor (MRTF)-A-dependent transactivation of smooth muscle a-actin, SM22a and cardiac atrial natriuretic factor (ANF) promoters in 10T1 ⁄ cells [116] Hamidouche et al [117] demonstrated that FHL2 interacts with b-catenin, a key player in bone formation induced by Wnt signaling, which potentiates b-catenin nuclear translocation and TCF ⁄ LEF transcription, resulting in increased Runx2 and alkaline phosphatase expression Human heart LIM protein (hhLIM) participates in remodeling of the actin cytoskeleton, possibly by promoting actin bundling [118] hhLIM has a dual subcellular location, depending on the context In the cytoplasm, hhLIM increases the stability of the actin cytoskeleton by promoting bundling of actin filaments [114] In the nucleus, hhLIM interacts with Nkx2.5 (a cardiac-restricted transcription factor) via its N-terminal LIM domain and enhances the ability of Nkx2.5 to bind to the NKE (Nkx2.5-binding element) boxes in the ANF promoter These results suggest that hhLIM promotes specific expression of the ANF gene by cooperating with Nkx2.5 [119] Muscle LIM protein (MLP) has been found in the nucleus during early development [120], where it is a potent activator of the myogenic regulatory factor myoD [121,122] Lu et al [123] showed that MLP promotes specific expression of the AChR gamma-subunit gene cooperatively with the myogenin–E12 complex during myogenesis FEBS Journal 276 (2009) 2669–2685 ª 2009 The Authors Journal compilation ª 2009 FEBS 2679 Actin and ABPs in transcription regulation B Zheng et al In addition, two ABPs, RPABC-2 and -3, are present in all three RNA polymerases, and the solution of the crystal structure of Pol II shows that these two subunits are located close to each other at the surface of the polymerase [29,124] and participate in the transcription initiation RPABC-2 and -3 form an actinbinding patch that is common to all three RNA polymerases and identify the same function Conclusions and perspectives The findings reported clearly show that ABPs participate in muscle-specific gene expression, AR transport and the formation of transcription complexes This aspect of ABPs is entirely novel and would not have been predicted 10 years ago As an interesting note, modulation of nuclear ABPs on target gene expression offers a feasible target for developing new therapeutic agents For example, because ABPs interact physically with the AR to modulate its transcriptional activity, disruption of the AR–ABP interaction may be an important strategy by which to regulate AR-mediated growth of prostate cancer cells The expression of selective ABPs may offer a growth advantage to tumor cells in androgen ablation and ⁄ or anti-androgen therapy We also predict that future work in this field will continue to uncover new properties of ABPs, revealing not only unexpected roles in the nucleus, but also the way in which they shuttle between cell compartments This exciting area of research will require more detailed investigation Acknowledgements This work was supported by the Program for Major State Basic Research Development Program of China (No 2008CB517402), the National Natural Science Foundation of the People’s Republic of China (No 30770787, 30670845, 30871272), the New Century Excellent Talents in University (No NCET-05-0261), the Key Project of Chinese Ministry of Education (No 206016), and the Hebei Natural Science Foundation of the People’s Republic of China (No C2008001049) This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging References Chen H, Bernstein BW & Bamburg JR (2000) Regulating actin-filament dynamics in vivo Trends Biochem Sci 25, 19–23 2680 Carlier MF, Le Clainche C, Wiesner S & Pantaloni D (2003) Actin-based motility: from molecules to movement BioEssays 25, 336–345 Sotiropoulos A, Gineitis D, Copeland J & Treisman R (1999) Signal-regulated activation of serum response factor is mediated by changes in actin dynamics Cell 98, 159–169 Grummt I (2006) Actin and myosin as transcription 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receptor; LBD, ligand-binding domain... STARS-interacting proteins These novel proteins contain four LIM domains and a C-terminal villin headpiece domain, which mediates actin- binding in several proteins, such as villin and dematin [59] Both... [24,27,29,35–38] Actin and ABPs in transcription regulation It is generally accepted that chromatin-remodeling complexes contain actin, actin- related proteins and ⁄ or ABPs Nuclear actin- related proteins

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