The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Anne H Monsoroburq - One of the best experts on this subject based on the ideXlab platform.
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bmp signaling is enhanced intracellularly by FHL3 controlling wnt dependent spatiotemporal emergence of the neural crest
Cell Reports, 2021Co-Authors: Mansour Alkobtawi, Patrick Pla, Anne H MonsoroburqAbstract:Summary The spatiotemporal coordination of multiple morphogens is essential for embryonic patterning yet poorly understood. During neural crest (NC) formation, dynamic bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and WNT signals cooperate by acting on mesoderm and ectoderm. Here, we show that FHL3, a scaffold LIM domain protein, modulates BMP gradient interpretation during NC induction. During gastrulation, low BMP signaling neuralizes the neural border (NB) ectoderm, while FHL3 enhances Smad1 intracellular response in underlying paraxial mesoderm, triggering the high WNT8 signals needed to pattern the NB. During neurulation, FHL3 activation in NC ectoderm promotes simultaneous high BMP and BMP-dependent WNT activity required for specification. Mechanistically, FHL3 interacts with Smad1 and promotes Smad1 binding to wnt8 promoter in a BMP-dependent manner. Consequently, differential FHL3 expression in adjacent cells ensures a finely tuned coordination of BMP and WNT signaling at several stages of NC development, starting by positioning the NC-inducing mesoderm center under competent NB ectoderm.
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intracellular enhancement of bmp signaling by lim domain protein FHL3 controls spatiotemporal emergence of the neural crest driven by wnt signaling
Social Science Research Network, 2020Co-Authors: Mansour Alkobtawi, Patrick Pla, Anne H MonsoroburqAbstract:How multiple morphogens are coordinated in space and time to position key embryonic tissues remains elusive. During neural crest formation, bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and WNT signaling cooperate by acting either on the paraxial mesoderm or directly on the neural border ectoderm, but how each tissue interprets this complex information remains poorly understood. Here we show that FHL3, a scaffold LIM domain protein of previously unknown developmental function, is essential for neural crest formation by linking BMP and WNT signaling thereby positioning the neural crest-inducing signaling center in the paraxial mesoderm. During gastrulation, FHL3 promotes Smad phosphorylation and Smad-dependent wnt8 activation in the paraxial mesoderm, thus enhancing the response of mesoderm compared to ectoderm although both germ layers are subjected to a common extracellular BMP gradient. This promotes a non-cell autonomous WNT signaling ensuring neural border ectoderm specification by the underlying mesoderm. During neurulation, in turn, neural crest inducers activate FHL3 in the ectoderm, promoting BMP/Smad-dependent WNT activity required for neural crest specification. We show that FHL3 binds Smads downstream of BMP signals and promotes Smad binding to wnt8 regulatory elements. Our findings highlight how FHL3, acting cell-autonomously, ensures a fine spatial and temporal coordination of BMP and WNT signaling at several steps of neural crest development.
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intracellular enhancement of bmp signaling by lim domain protein FHL3 controls spatiotemporal emergence of the neural crest driven by wnt signaling
bioRxiv, 2019Co-Authors: Mansour Alkobtawi, Patrick Pla, Anne H MonsoroburqAbstract:Abstract How multiple morphogen signals are coordinated in space and time to position key embryonic tissues remains elusive. During neural crest formation, bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and WNT signaling cooperate by acting either on the paraxial mesoderm or directly on the neural border ectoderm, but how each tissue interprets this complex information remains poorly understood. Here we show that FHL3, a scaffold LIM domain protein of previously unknown developmental function, is essential for neural crest formation by linking BMP and WNT signaling thereby positioning the neural crest-inducing signaling center in the paraxial mesoderm. During gastrulation, FHL3 promotes Smad phosphorylation and Smad-dependent wnt8 activation specifically in the paraxial mesoderm, thus modifying the respective mesoderm or ectoderm cell response to the extracellular BMP gradient. This ensures neural border ectoderm specification by the underlying mesoderm via non-cell autonomous WNT signaling. During neurulation, neural crest inducers activate FHL3, promoting BMP/Smad-dependent WNT activity required for neural crest specification. Our findings highlight how FHL3, acting cell-autonomously, ensures a fine spatial, temporal and germ layer-specific coordination of BMP and WNT signaling at several steps of neural crest development. Highlights: -FHL3 is a novel intracellular enhancer of BMP signaling during early development. -FHL3 ensures cross-talk between BMP and WNT signaling by Smad1-dependent wnt8 activation in the paraxial mesoderm. -FHL3 reiterated function in paraxial mesoderm and in neural border ectoderm is essential for neural crest development at the border of the neural plate.
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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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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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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expression patterns of fhl slim family members suggest important functional roles in skeletal muscle and cardiovascular system
Mechanisms of Development, 2000Co-Authors: Pilar Ruizlozano, Qiang Zhou, Ju ChenAbstract:Abstract LIM domain containing proteins play critical roles in animal development and cellular differentiation. Here, we describe the cloning and expression patterns of three members of the four and a half LIM domain-only protein family, FHL1, 2, and 3, from mouse. A comparison of embryonic expression patterns of these three highly-related genes indicates that they are expressed in an overlapping pattern in the developing cardiovascular system, and skeletal muscle. In adult tissues, the three genes are expressed in a predominant and overlapping manner in cardiac and skeletal muscle. Of the three genes, FHL2 appears to have the most restricted expression pattern during development, in heart, blood vessels, and skeletal muscle. Expression in heart is highest in cardiac septa and in the region adjacent to the atrio-ventricular ring, suggesting a potential role in septation or conduction system development. In the heart, FHL1expression was observed strongly in developing outflow tract, and to a lesser extent in myocardium. FHL3 displays low and ubiquitous expression during mouse development. Cardiac ventricular expression of FHL1, but not FHL2 or FHL3, was upregulated in two mouse models of cardiac hypertrophic and dilated cardiomyopathy. Taken together, these data indicate the potential importance of this FHL family in the development and maintenance of the cardiovascular system and striated muscle, and suggest that FHL1 may play a role in the development of heart disease.
Jennifer Dahan - 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 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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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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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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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.
Charlotte Labalette - One of the best experts on this subject based on the ideXlab platform.
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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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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.
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identification of the lim protein fhl2 as a coactivator of β catenin
Journal of Biological Chemistry, 2003Co-Authors: Yu Wei, Charlotte Labalette, Claire-angélique Renard, Christine Neuveut, Laurence Levy, Xavier Prieur, Marc Flajolet, Sylvie Prigent, Marieannick BuendiaAbstract:β-Catenin is a key mediator of the Wnt pathway, which plays a critical role in embryogenesis and oncogenesis. As a transcriptional activator, β-catenin binds the transcription factors, T-cell factor and lymphoid enhancer factor, and regulates gene expression in response to Wnt signaling. Abnormal activation of β-catenin has been linked to various types of cancer. In a yeast two-hybrid screen, we identified the four and a half of LIM-only protein 2 (FHL2) as a novel β-catenin-interacting protein. Here we show specific interaction of FHL2 with β-catenin, which requires the intact structure of FHL2 and armadillo repeats 1–9 of β-catenin. FHL2 cooperated with β-catenin to activate T-cell factor/lymphoid enhancer factor-dependent transcription from a synthetic reporter and the cyclin D1 and interleukin-8 promoters in kidney and colon cell lines. In contrast, coexpression of β-catenin and FHL2 had no synergistic effect on androgen receptor-mediated transcription, whereas each of these two coactivators independently stimulated AR transcriptional activity. Thus, the ability of FHL2 to stimulate the trans-activating function of β-catenin might be dependent on the promoter context. The detection of increased FHL2 expression in hepatoblastoma, a liver tumor harboring frequent β-catenin mutations, suggests that FHL2 might enforce β-catenin transactivation activity in cancer cells. These findings reveal a new function of the LIM coactivator FHL2 in transcriptional activation of Wnt-responsive genes.