The Experts below are selected from a list of 5730 Experts worldwide ranked by ideXlab platform
Akiko Hata - One of the best experts on this subject based on the ideXlab platform.
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the four and a half lim domain protein 2 regulates vascular smooth muscle phenotype and vascular tone
Journal of Biological Chemistry, 2009Co-Authors: Nicole A Neuman, Gavin R Schnitzler, Yan Zhu, Giorgio Lagna, Akiko HataAbstract:In response to vascular injury, differentiated vascular smooth muscle cells (vSMCs) undergo a unique process known as "phenotype modulation," transitioning from a quiescent, "contractile" phenotype to a proliferative, "synthetic" state. We have demonstrated previously that the signaling pathway of bone morphogenetic proteins, members of the transforming growth factor beta family, play a role in the induction and maintenance of a contractile phenotype in human primary pulmonary artery smooth muscle cells. In this study, we show that a four-and-a-half LIM domain protein 2 (FHL2) inhibits transcriptional activation of vSMC-specific genes mediated by the bone morphogenetic protein signaling pathway through the CArG box-binding proteins, such as serum response factor and members of the myocardin (Myocd) family. Interestingly, FHL2 does not affect recruitment of serum response factor or Myocd, however, it inhibits recruitment of a component of the SWI/SNF chromatin remodeling complex, Brg1, and RNA polymerase II, which are essential for the transcriptional activation. This is a novel mechanism of regulation of SMC-specific contractile genes by FHL2. Finally, aortic rings from homozygous FHL2-null mice display abnormalities in both endothelial-dependent and -independent relaxation, suggesting that FHL2 is essential for the regulation of vasomotor tone.
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the four and a half lim domain protein 2 regulates vascular smooth muscle phenotype and vascular tone
Journal of Biological Chemistry, 2009Co-Authors: Nicole A Neuman, Gavin R Schnitzler, Giorgio Lagna, Akiko HataAbstract:Abstract In response to vascular injury, differentiated vascular smooth muscle cells (vSMCs) undergo a unique process known as “phenotype modulation,” transitioning from a quiescent, “contractile” phenotype to a proliferative, “synthetic” state. We have demonstrated previously that the signaling pathway of bone morphogenetic proteins, members of the transforming growth factor β family, play a role in the induction and maintenance of a contractile phenotype in human primary pulmonary artery smooth muscle cells. In this study, we show that a four-and-a-half LIM domain protein 2 (FHL2) inhibits transcriptional activation of vSMC-specific genes mediated by the bone morphogenetic protein signaling pathway through the CArG box-binding proteins, such as serum response factor and members of the myocardin (Myocd) family. Interestingly, FHL2 does not affect recruitment of serum response factor or Myocd, however, it inhibits recruitment of a component of the SWI/SNF chromatin remodeling complex, Brg1, and RNA polymerase II, which are essential for the transcriptional activation. This is a novel mechanism of regulation of SMC-specific contractile genes by FHL2. Finally, aortic rings from homozygous FHL2-null mice display abnormalities in both endothelial-dependent and -independent relaxation, suggesting that FHL2 is essential for the regulation of vasomotor tone.
Florence Levillayer - One of the best experts on this subject based on the ideXlab platform.
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LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression
Molecular and Cellular Biology, 2017Co-Authors: Jennifer Dahan, Yann Nouet, Florence Levillayer, Tian Xia, Catherine Werts, Martine Fanton D'andon, Minou Adib-conquy, Anne-marie Cassard-doulcier, Varun Khanna, Ju ChenAbstract:Transforming growth factor β1 (TGF-β1) is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair. Here, we report that four and a half LIM-only protein 2 (FHL2) is a critical regulator of TGF-β1 expression. Devoid of a DNA-binding domain, FHL2 is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts. We detected association of FHL2 with the TGF-β1 promoter, which showed higher activity in FHL2-/- cells than in wild-type (WT) cells in a reporter assay. Overexpression of FHL2 abrogates the activation of the TGF-β1 promoter, whereas the upregulation of TGF-β1 gene transcription correlates with reduced occupancy of FHL2 on the promoter. Moreover, ablation of FHL2 facilitates recruitment of RNA polymerase II on the TGF-β1 promoter, suggesting that FHL2 may be involved in chromatin remodeling in the control of TGF-β1 gene transcription. Enhanced expression of TGF-β1 mRNA and cytokine was evidenced in the livers of FHL2-/- mice. We tested the in vivo impact of FHL2 loss on hepatic fibrogenesis that involves TGF-β1 activation. FHL2-/- mice developed more severe fibrosis than their WT counterparts. These results demonstrate the repressive function of FHL2 on TGF-β1 expression and contribute to the understanding of the TGF-β-mediated fibrogenic response.
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LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis.
Molecular and Cellular Biology, 2013Co-Authors: Jennifer Dahan, Yann Nouet, Florence Levillayer, Gregory Jouvion, Minou Adib-conquy, Anne-marie Cassard-doulcier, Ali Tebbi, Fany Blanc, Lauriane Remy, Ju ChenAbstract:Four-and-a-half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in nuclear factor κB (NF-κB) signaling in the liver. We show that FHL2 enhanced tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) activity in transcriptional activation of NF-κB targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NF-κB pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-κB activity, which regulates expression of inflammatory cytokines. Indeed, FHL2(-/-) macrophages showed significantly reduced production of TNF and interleukin 6 (IL-6) following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2(-/-) mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-κB signaling orchestrates inflammatory cross talk between hepatocytes and hepatic immune cells that promote chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-κB signaling. Our findings demonstrate FHL2 as a positive regulator of NF-κB activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells.
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the four and a half lim only protein 2 FHL2 activates transforming growth factor β tgf β signaling by regulating ubiquitination of the e3 ligase arkadia
Journal of Biological Chemistry, 2013Co-Authors: Tian Xia, Florence Levillayer, Marieannick Buendia, Christine Neuveut, Laurence Levy, Baosen Jia, Ke Lan, Yu WeiAbstract:Arkadia is a RING-based ubiquitin ligase that positively regulates TGF-β signaling by targeting several pathway components for ubiquitination and degradation. However, little is known about the mechanisms controlling Arkadia activity. Here we show that the LIM-only protein FHL2 binds and synergistically cooperates with Arkadia to activate Smad3/Smad4-dependent transcription. Knockdown of FHL2 by RNA interference decreases Arkadia level and restricts the amplitude of Arkadia-induced TGF-β target gene responses. We found that Arkadia is ubiquitinated via K63- and K27-linked polyubiquitination. A single mutation at the RING domain that abolishes the E3 activity diminishes Arkadia ubiquitination, indicating that this modification partly involves autocatalytic process. Mutation of seven lysines at the C-terminal region of Arkadia severely impairs ubiquitination through the K27 but not the K63 linkage and slows down the turnover of Arkadia, suggesting that K27-linked polyubiquitination might promote proteolysis-dependent regulation of Arkadia. We show that FHL2 increases the half-life of Arkadia through inhibition of ubiquitin chain assembly on the protein, which provides a molecular basis for functional cooperation between Arkadia and FHL2 in enhancing TGF-β signaling. Our study uncovers a novel regulatory mechanism of Arkadia by ubiquitination and identifies FHL2 as important regulator of Arkadia ubiquitination and TGF-β signal transduction.
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Loss of FHL2 reduces intestinal polyp multiplicity.
2013Co-Authors: Charlotte Labalette, Yann Nouet, Florence Levillayer, Marieannick Buendia, Ju Chen, Sabine Colnot, Valere Claude, Michel Huerre, Christine Perret, Yu WeiAbstract:(A) Representative images of intestines from 11-month-old ApcΔ14/+FHL2+/+ and ApcΔ14/+FHL2−/− mouse. Note the marked decrease in the number of polyps in ApcΔ14/+FHL2−/− mice. (B) Total number of intestinal polyps was counted in 11 ApcΔ14/+FHL2+/+, 16 ApcΔ14/+FHL2−/+ and 18 ApcΔ14/+FHL2−/− mice at 11-month-old. Compared to ApcΔ14/+FHL2+/+ littermates, significant reduction in polyp number was observed in ApcΔ14/+FHL2−/+ (p
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the four and a half lim only protein 2 regulates liver homeostasis and contributes to carcinogenesis
Journal of Hepatology, 2012Co-Authors: Yann Nouet, Florence Levillayer, Charlotte Labalette, Jennifer Dahan, Boris Julien, Gregory JouvionAbstract:Background & Aims The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice ( Apo-FHL2 ). Methods We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2 ; Apc lox/lox mice. Results Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc lox/lox animals. Conclusions Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.
Yann Nouet - One of the best experts on this subject based on the ideXlab platform.
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LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression
Molecular and Cellular Biology, 2017Co-Authors: Jennifer Dahan, Yann Nouet, Florence Levillayer, Tian Xia, Catherine Werts, Martine Fanton D'andon, Minou Adib-conquy, Anne-marie Cassard-doulcier, Varun Khanna, Ju ChenAbstract:Transforming growth factor β1 (TGF-β1) is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair. Here, we report that four and a half LIM-only protein 2 (FHL2) is a critical regulator of TGF-β1 expression. Devoid of a DNA-binding domain, FHL2 is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts. We detected association of FHL2 with the TGF-β1 promoter, which showed higher activity in FHL2-/- cells than in wild-type (WT) cells in a reporter assay. Overexpression of FHL2 abrogates the activation of the TGF-β1 promoter, whereas the upregulation of TGF-β1 gene transcription correlates with reduced occupancy of FHL2 on the promoter. Moreover, ablation of FHL2 facilitates recruitment of RNA polymerase II on the TGF-β1 promoter, suggesting that FHL2 may be involved in chromatin remodeling in the control of TGF-β1 gene transcription. Enhanced expression of TGF-β1 mRNA and cytokine was evidenced in the livers of FHL2-/- mice. We tested the in vivo impact of FHL2 loss on hepatic fibrogenesis that involves TGF-β1 activation. FHL2-/- mice developed more severe fibrosis than their WT counterparts. These results demonstrate the repressive function of FHL2 on TGF-β1 expression and contribute to the understanding of the TGF-β-mediated fibrogenic response.
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LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis.
Molecular and Cellular Biology, 2013Co-Authors: Jennifer Dahan, Yann Nouet, Florence Levillayer, Gregory Jouvion, Minou Adib-conquy, Anne-marie Cassard-doulcier, Ali Tebbi, Fany Blanc, Lauriane Remy, Ju ChenAbstract:Four-and-a-half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in nuclear factor κB (NF-κB) signaling in the liver. We show that FHL2 enhanced tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) activity in transcriptional activation of NF-κB targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NF-κB pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-κB activity, which regulates expression of inflammatory cytokines. Indeed, FHL2(-/-) macrophages showed significantly reduced production of TNF and interleukin 6 (IL-6) following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2(-/-) mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-κB signaling orchestrates inflammatory cross talk between hepatocytes and hepatic immune cells that promote chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-κB signaling. Our findings demonstrate FHL2 as a positive regulator of NF-κB activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells.
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Loss of FHL2 reduces intestinal polyp multiplicity.
2013Co-Authors: Charlotte Labalette, Yann Nouet, Florence Levillayer, Marieannick Buendia, Ju Chen, Sabine Colnot, Valere Claude, Michel Huerre, Christine Perret, Yu WeiAbstract:(A) Representative images of intestines from 11-month-old ApcΔ14/+FHL2+/+ and ApcΔ14/+FHL2−/− mouse. Note the marked decrease in the number of polyps in ApcΔ14/+FHL2−/− mice. (B) Total number of intestinal polyps was counted in 11 ApcΔ14/+FHL2+/+, 16 ApcΔ14/+FHL2−/+ and 18 ApcΔ14/+FHL2−/− mice at 11-month-old. Compared to ApcΔ14/+FHL2+/+ littermates, significant reduction in polyp number was observed in ApcΔ14/+FHL2−/+ (p
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the four and a half lim only protein 2 regulates liver homeostasis and contributes to carcinogenesis
Journal of Hepatology, 2012Co-Authors: Yann Nouet, Florence Levillayer, Charlotte Labalette, Jennifer Dahan, Boris Julien, Gregory JouvionAbstract:Background & Aims The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice ( Apo-FHL2 ). Methods We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2 ; Apc lox/lox mice. Results Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc lox/lox animals. Conclusions Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.
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deficiency of the lim only protein FHL2 reduces intestinal tumorigenesis in apc mutant mice
PLOS ONE, 2010Co-Authors: Yann Nouet, Florence Levillayer, Charlotte Labalette, Ju Chen, Sabine Colnot, Valere Claude, Michel HuerreAbstract:Background The four and a half LIM-only protein 2 (FHL2) is capable of shuttling between focal adhesion and nucleus where it signals through direct interaction with a number of proteins including β-catenin. Although FHL2 activation has been found in various human cancers, evidence of its functional contribution to carcinogenesis has been lacking.
Charlotte Labalette - One of the best experts on this subject based on the ideXlab platform.
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Loss of FHL2 reduces intestinal polyp multiplicity.
2013Co-Authors: Charlotte Labalette, Yann Nouet, Florence Levillayer, Marieannick Buendia, Ju Chen, Sabine Colnot, Valere Claude, Michel Huerre, Christine Perret, Yu WeiAbstract:(A) Representative images of intestines from 11-month-old ApcΔ14/+FHL2+/+ and ApcΔ14/+FHL2−/− mouse. Note the marked decrease in the number of polyps in ApcΔ14/+FHL2−/− mice. (B) Total number of intestinal polyps was counted in 11 ApcΔ14/+FHL2+/+, 16 ApcΔ14/+FHL2−/+ and 18 ApcΔ14/+FHL2−/− mice at 11-month-old. Compared to ApcΔ14/+FHL2+/+ littermates, significant reduction in polyp number was observed in ApcΔ14/+FHL2−/+ (p
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the four and a half lim only protein 2 regulates liver homeostasis and contributes to carcinogenesis
Journal of Hepatology, 2012Co-Authors: Yann Nouet, Florence Levillayer, Charlotte Labalette, Jennifer Dahan, Boris Julien, Gregory JouvionAbstract:Background & Aims The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice ( Apo-FHL2 ). Methods We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2 ; Apc lox/lox mice. Results Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc lox/lox animals. Conclusions Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.
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deficiency of the lim only protein FHL2 reduces intestinal tumorigenesis in apc mutant mice
PLOS ONE, 2010Co-Authors: Yann Nouet, Florence Levillayer, Charlotte Labalette, Ju Chen, Sabine Colnot, Valere Claude, Michel HuerreAbstract:Background The four and a half LIM-only protein 2 (FHL2) is capable of shuttling between focal adhesion and nucleus where it signals through direct interaction with a number of proteins including β-catenin. Although FHL2 activation has been found in various human cancers, evidence of its functional contribution to carcinogenesis has been lacking.
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the lim only protein FHL2 regulates cyclin d1 expression and cell proliferation
Journal of Biological Chemistry, 2008Co-Authors: Charlotte Labalette, Yann Nouet, Joelle Sobczakthepot, Florence Levillayer, Marieclaude Gendron, Claire-angélique Renard, Carolina Armengol, Béatrice Regnault, Ju Chen, Marieannick BuendiaAbstract:The LIM-only protein FHL2 acts as a transcriptional modulator that positively or negatively regulates multiple signaling pathways. We recently reported that FHL2 cooperates with CREB-binding protein/p300 in the activation of β-catenin/T cell factor target gene cyclin D1. In this paper, we demonstrate that FHL2 is associated with the cyclin D1 promoter at the T cell factor/CRE site, providing evidence that cyclin D1 is a direct target of FHL2. We show that deficiency of FHL2 greatly reduces the proliferative capacity of spontaneously immortalized mouse fibroblasts, which is associated with decreased expression of cyclin D1 and p16INK4a, and hypophosphorylation of Rb. Reexpression of FHL2 in FHL2-null fibroblasts efficiently restores cyclin D1 levels and cell proliferative capacity, indicating that FHL2 is critical for cyclin D1 activation and cell growth. Moreover, ectopic cyclin D1 expression is sufficient to override growth inhibition of immortalized FHL2-null fibroblasts. Gene expression profiling revealed that FHL2 deficiency triggers a broad change of the cell cycle program that is associated with down-regulation of several G1/S and G2/M cyclins, E2F transcription factors, and DNA replication machinery, thus correlating with reduced cell proliferation. This change also involves down-regulation of the negative cell cycle regulators, particularly INK4 inhibitors, which could counteract the decreased expression of cyclins, allowing cells to grow. Our study illustrates that FHL2 can act on different aspects of the cell cycle program to finely regulate cell proliferation.
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interaction and functional cooperation between the lim protein FHL2 cbp p300 and β catenin
Molecular and Cellular Biology, 2004Co-Authors: Charlotte Labalette, Marieannick Buendia, Claire-angélique Renard, Christine Neuveut, Yu WeiAbstract:Transcriptional activation of gene expression by Wnt signaling is driven by the association of β-catenin with TCF/LEF factors and the recruitment of transcriptional coactivators. It has been shown that the LIM protein FHL2 and the acetyltransferase CBP/p300 individually stimulate β-catenin transactivating activity and that β-catenin is acetylated by p300. Here, we report that FHL2 and CBP/p300 synergistically enhanced β-catenin/TCF-mediated transcription from Wnt-responsive promoters and that the acetyltransferase activity of CBP/p300 was involved in the cooperation. CBP/p300 interacted directly with FHL2, predominantly through the CH3 domain but not the histone acetyltransferase domain, and different regions of CBP/p300 were involved in FHL2 and β-catenin binding. We provided evidence for the formation of a ternary complex by FHL2, CBP/p300, and β-catenin and for colocalization of the three proteins in the nucleus. In murine FHL2−/− embryo fibroblasts, the transactivation activity of β-catenin/TCF was markedly reduced, and this defect could be restored by exogenous expression of FHL2. However, CBP/p300 were still able to coactivate the β-catenin/TCF complex in FHL2−/− cells, suggesting that FHL2 is dispensable for the coactivator function of CBP/p300 on β-catenin. Furthermore, we found that FHL2 significantly increased acetylation of β-catenin by p300 in vivo. Finally, we showed that FHL2, CBP/p300, and β-catenin could synergistically activate androgen receptor-mediated transcription, indicating that the synergistic coactivator function is not restricted to TCF/LEF.
Ju Chen - One of the best experts on this subject based on the ideXlab platform.
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LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression
Molecular and Cellular Biology, 2017Co-Authors: Jennifer Dahan, Yann Nouet, Florence Levillayer, Tian Xia, Catherine Werts, Martine Fanton D'andon, Minou Adib-conquy, Anne-marie Cassard-doulcier, Varun Khanna, Ju ChenAbstract:Transforming growth factor β1 (TGF-β1) is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair. Here, we report that four and a half LIM-only protein 2 (FHL2) is a critical regulator of TGF-β1 expression. Devoid of a DNA-binding domain, FHL2 is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts. We detected association of FHL2 with the TGF-β1 promoter, which showed higher activity in FHL2-/- cells than in wild-type (WT) cells in a reporter assay. Overexpression of FHL2 abrogates the activation of the TGF-β1 promoter, whereas the upregulation of TGF-β1 gene transcription correlates with reduced occupancy of FHL2 on the promoter. Moreover, ablation of FHL2 facilitates recruitment of RNA polymerase II on the TGF-β1 promoter, suggesting that FHL2 may be involved in chromatin remodeling in the control of TGF-β1 gene transcription. Enhanced expression of TGF-β1 mRNA and cytokine was evidenced in the livers of FHL2-/- mice. We tested the in vivo impact of FHL2 loss on hepatic fibrogenesis that involves TGF-β1 activation. FHL2-/- mice developed more severe fibrosis than their WT counterparts. These results demonstrate the repressive function of FHL2 on TGF-β1 expression and contribute to the understanding of the TGF-β-mediated fibrogenic response.
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LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis.
Molecular and Cellular Biology, 2013Co-Authors: Jennifer Dahan, Yann Nouet, Florence Levillayer, Gregory Jouvion, Minou Adib-conquy, Anne-marie Cassard-doulcier, Ali Tebbi, Fany Blanc, Lauriane Remy, Ju ChenAbstract:Four-and-a-half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in nuclear factor κB (NF-κB) signaling in the liver. We show that FHL2 enhanced tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) activity in transcriptional activation of NF-κB targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NF-κB pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-κB activity, which regulates expression of inflammatory cytokines. Indeed, FHL2(-/-) macrophages showed significantly reduced production of TNF and interleukin 6 (IL-6) following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2(-/-) mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-κB signaling orchestrates inflammatory cross talk between hepatocytes and hepatic immune cells that promote chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-κB signaling. Our findings demonstrate FHL2 as a positive regulator of NF-κB activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells.
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Loss of FHL2 reduces intestinal polyp multiplicity.
2013Co-Authors: Charlotte Labalette, Yann Nouet, Florence Levillayer, Marieannick Buendia, Ju Chen, Sabine Colnot, Valere Claude, Michel Huerre, Christine Perret, Yu WeiAbstract:(A) Representative images of intestines from 11-month-old ApcΔ14/+FHL2+/+ and ApcΔ14/+FHL2−/− mouse. Note the marked decrease in the number of polyps in ApcΔ14/+FHL2−/− mice. (B) Total number of intestinal polyps was counted in 11 ApcΔ14/+FHL2+/+, 16 ApcΔ14/+FHL2−/+ and 18 ApcΔ14/+FHL2−/− mice at 11-month-old. Compared to ApcΔ14/+FHL2+/+ littermates, significant reduction in polyp number was observed in ApcΔ14/+FHL2−/+ (p
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the lim only protein FHL2 controls mesenchymal cell osteogenic differentiation and bone formation through wnt5a and wnt10b
Bone, 2012Co-Authors: Ju Chen, Julia Brun, Olivia Fromigue, Francoisxavier Dieudonne, Caroline Marty, Jennifer DahanAbstract:Wnt signaling is an important pathway that controls the osteogenic differentiation of mesenchymal stromal cells (MSC). We previously showed that FHL2, a LIM-only protein with four and a half LIM domains, controls MSC osteogenic differentiation via the canonical Wnt/β-catenin signaling. In this study, we investigated the role of Wnt proteins in the regulation of MSC differentiation by FHL2. We found that Wnt3a increased FHL2 mRNA expression in murine C3H10T1/2 mesenchymal cells. Silencing FHL2 using short hairpin (sh) RNA attenuated β-catenin transcriptional activity and osteogenic differentiation induced by Wnt3a. In addition, FHL2 silencing reduced the expression of the key molecules Wnt5a and Wnt10b and osteoblast gene expression. Wnt10b overcomes the negative effect of FHL2 knockdown on osteoblast gene expression in vitro. To confirm this finding in vivo, we analyzed the expression of these Wnt molecules in FHL2 deficient mice. Histomorphometric analyses showed that FHL2 knockout decreased trabecular number and thickness and reduced bone mass in 15-month old mice. This phenotype was associated with decreased Wnt5a and Wnt10b and lower than normal c-myc, cyclin D1 and osteoblast gene expression in the bone marrow. Ex vivo analysis showed decreased basal and Wnt3a-induced Wnt5a and Wnt10b mRNA expression in FHL2-deficient bone marrow cells, further indicating that this defect may contribute to the reduced osteoblast function in FHL2 deficient mice. In contrast, the decreased adipogenesis induced by FHL2 deficiency in vitro and in vivo was linked to increased Foxo1 expression. Collectively, the results provide evidence for a previously unrecognized mechanism by which FHL2 controls the osteogenic differentiation of MSC, bone formation and bone mass through modulation of Wnt molecules.
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deficiency of the lim only protein FHL2 reduces intestinal tumorigenesis in apc mutant mice
PLOS ONE, 2010Co-Authors: Yann Nouet, Florence Levillayer, Charlotte Labalette, Ju Chen, Sabine Colnot, Valere Claude, Michel HuerreAbstract:Background The four and a half LIM-only protein 2 (FHL2) is capable of shuttling between focal adhesion and nucleus where it signals through direct interaction with a number of proteins including β-catenin. Although FHL2 activation has been found in various human cancers, evidence of its functional contribution to carcinogenesis has been lacking.