The Experts below are selected from a list of 91863 Experts worldwide ranked by ideXlab platform
Martin M Matzuk - One of the best experts on this subject based on the ideXlab platform.
-
Growth Differentiation Factor 9 bone morphogenetic protein 15 heterodimers are potent regulators of ovarian functions
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Jia Peng, Karen Wigglesworth, Adithya Rangarajan, Chandramohan Kattamuri, Randall T Peterson, John J Eppig, Thomas B Thompson, Martin M MatzukAbstract:The TGF-β superfamily is the largest family of secreted proteins in mammals, and members of the TGF-β family are involved in most developmental and physiological processes. Growth Differentiation Factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), oocyte-secreted paralogs of the TGF-β superfamily, have been shown genetically to control ovarian physiology. Although previous studies found that GDF9 and BMP15 homodimers can modulate ovarian pathways in vitro, the functional species-specific significance of GDF9:BMP15 heterodimers remained unresolved. Therefore, we engineered and produced purified recombinant mouse and human GDF9 and BMP15 homodimers and GDF9:BMP15 heterodimers to compare their molecular characteristics and physiological functions. In mouse granulosa cell and cumulus cell expansion assays, mouse GDF9 and human BMP15 homodimers can up-regulate cumulus expansion-related genes (Ptx3, Has2, and Ptgs2) and promote cumulus expansion in vitro, whereas mouse BMP15 and human GDF9 homodimers are essentially inactive. However, we discovered that mouse GDF9:BMP15 heterodimer is ∼10- to 30-fold more biopotent than mouse GDF9 homodimer, and human GDF9:BMP15 heterodimer is ∼1,000- to 3,000-fold more bioactive than human BMP15 homodimer. We also demonstrate that the heterodimers require the kinase activities of ALK4/5/7 and BMPR2 to activate SMAD2/3 but unexpectedly need ALK6 as a coreceptor in the signaling complex in granulosa cells. Our findings that GDF9:BMP15 heterodimers are the most bioactive ligands in mice and humans compared with homodimers explain many puzzling genetic and physiological data generated during the last two decades and have important implications for improving female fertility in mammals.
-
knockout of pentraxin 3 a downstream target of Growth Differentiation Factor 9 causes female subfertility
Molecular Endocrinology, 2002Co-Authors: Simona Varani, Janet L Demayo, Heidi F. Horton, Michael C. Byrne, Francesco J Demayo, Julia A Elvin, Martin M MatzukAbstract:The ovulatory process is tightly regulated by endocrine as well as paracrine Factors. In the periovulatory period, extensive remodeling of the follicle wall occurs to allow the extrusion of the oocyte and accompanying cumulus granulosa cells. Growth Differentiation Factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15) are secreted members of the TGFβ superfamily that are expressed beginning in the oocyte of small primary follicles and through ovulation. Besides its critical role as a Growth and Differentiation Factor during early folliculogenesis, GDF-9 also acts as a paracrine Factor to regulate several key events in preovulatory follicles. By analyzing GDF-9-regulated expression profiles using gene chip technology, we identified TNF-induced protein 6 (Tnfip6) and pentraxin 3 (Ptx3 or PTX3) as novel Factors induced by GDF-9 in granulosa cells of preovulatory follicles. Whereas Tnfip6 is induced in all granulosa cells by the LH surge, Ptx3 expression in the ovary is specifically observed after the L...
-
molecular characterization of the follicle defects in the Growth Differentiation Factor 9 deficient ovary
Molecular Endocrinology, 1999Co-Authors: Julia A Elvin, Katsuhiko Nishimori, Changning Yan, Pei Wang, Martin M MatzukAbstract:Growth Differentiation Factor-9 (GDF-9), a secreted member of the transforming Growth Factor-β superfamily, is expressed at high levels in the mammalian oocyte beginning at the type 3a primary follicle stage. We have previously demonstrated that GDF-9-deficient female mice are infertile because of an early block in folliculogenesis at the type 3b primary follicle stage. To address the molecular defects that result from the absence of GDF-9, we have analyzed the expression of several important ovarian marker genes. The major findings of our studies are as follows: 1) There are no detectable signals around GDF-9-deficient follicles for several theca cell layer markers [i.e. 17α-hydroxylase, LH receptor (LHR), and c-kit, the receptor for kit ligand]. This demonstrates that in the absence of GDF-9, the follicles are incompetent to emit a signal that recruits theca cell precursors to surround the follicle; 2) The primary follicles of GDF-9-deficient mice demonstrate an up-regulation of kit ligand and inhibin-α...
-
paracrine actions of Growth Differentiation Factor 9 in the mammalian ovary
Molecular Endocrinology, 1999Co-Authors: Julia A Elvin, Pei Wang, Amander T Clark, Neil M Wolfman, Martin M MatzukAbstract:Although the transforming Growth Factor-beta (TGF-beta) superfamily is the largest family of secreted Growth Factors, surprisingly few downstream target genes in their signaling pathways have been identified. Likewise, the identities of oocyte-derived secreted Factors, which regulate important oocyte-somatic cell interactions, remain largely unknown. For example, oocytes are known to secrete paracrine Growth Factor(s) which are necessary for cumulus expansion, induction of hyaluronic acid synthesis, and suppression of LH receptor (LHR) mRNA synthesis. Our previous studies demonstrated that absence of the TGF-beta family member, Growth Differentiation Factor-9 (GDF-9), blocks ovarian folliculogenesis at the primary follicle stage leading to infertility. In the present study, we demonstrate that mouse GDF-9 protein is expressed in all oocytes beginning at the type 3a follicle stage including antral follicles. To explore the biological functions of GDF-9 in the later stages of folliculogenesis and cumulus expansion, we produced mature, glycosylated, recombinant mouse GDF-9 using a Chinese hamster ovary cell expression system. A granulosa cell culture system was established to determine the role of GDF-9 in the regulation of several key ovarian gene products using semiquantitative RT-PCR. We find that recombinant GDF-9 induces hyaluronan synthase 2 (HAS2), cyclooxygenase 2 (COX-2), and steroidogenic acute regulator protein (StAR) mRNA synthesis but suppresses urokinase plasminogen activator (uPA) and LHR mRNA synthesis. Consistent with the induction of StAR mRNA by GDF-9, recombinant GDF-9 increases granulosa cell progesterone synthesis in the absence of FSH. Since induction of HAS2 and suppression of the protease uPA in cumulus cells are key events in the production of the hyaluronic acid-rich extracellular matrix which is produced during cumulus expansion, we determined whether GDF-9 could mimic this process. Using oocytectomized cumulus cell-oocyte complexes, we show that recombinant GDF-9 induces cumulus expansion in vitro. These studies demonstrate that GDF-9 can bind to receptors on granulosa cells to regulate the expression of a number of gene products. Thus, in addition to playing a critical function as a Growth and Differentiation Factor during early folliculogenesis, GDF-9 functions as an oocyte-secreted paracrine Factor to regulate several key granulosa cell enzymes involved in cumulus expansion and maintenance of an optimal oocyte microenvironment, processes which are essential for normal ovulation, fertilization, and female reproduction.
-
characterization of oocyte and follicle development in Growth Differentiation Factor 9 deficient mice
Developmental Biology, 1998Co-Authors: Mary Jo Carabatsos, Julia A Elvin, Martin M Matzuk, David F AlbertiniAbstract:Female mice null for the oocyte-specific gene product, Growth Differentiation Factor-9 (GDF-9), a member of the transforming Growth Factor-beta superfamily, exhibit primary infertility due to failed ovarian follicular development. The purpose of this study is to characterize oocyte and follicular Differentiation as a function of animal age using cell culture and fluorescence, confocal, and electron microscopy. Analysis of follicles from GDF-9 homozygous mutant mice indicates that GDF-9-deficient oocytes grow more rapidly than control oocytes and that follicle Growth ceases at the type 3b stage. Based on germinal vesicle (GV) chromatin patterns, fully grown oocytes isolated from GDF-9-deficient mice progress to advanced stages of Differentiation equivalent to those found in antral follicles of control (heterozygous) mice. In vitro maturation of oocytes from homozygous mutant mice revealed that most oocytes are capable of resuming meiosis, with the ability to achieve meiotic completion reaching the highest levels in 6-week-old mice. Among the characteristic ultrastructural features of oocytes from homozygous mutant mice are perinuclear organelle aggregation, unusual peripheral Golgi complexes, and a failure to form cortical granules. Modified interconnections between granulosa cells and oocytes were also observed by ultrastructural (EM) and fluorescence microscopic analysis of follicles from GDF-9-deficient mice. These modifications included a decrease in the number of actin-based transzonal processes and modifications of microtubule-based projections that over time gave rise to invasion of the perivitelline space with eventual loss of oocyte viability. These cell-cell aberrations suggest a critical role for GDF-9 in the regulation of Growth in preantral follicles through a mechanism involving bidirectional somatic cell-germ cell interactions.
Tibor Kempf - One of the best experts on this subject based on the ideXlab platform.
-
Growth Differentiation Factor 15 as a biomarker in cardiovascular disease
Clinical Chemistry, 2017Co-Authors: Kai C Wollert, Tibor Kempf, Lars WallentinAbstract:BACKGROUND: Growth Differentiation Factor 15 (GDF-15) is expressed and secreted in response to inflammation, oxidative stress, hypoxia, telomere erosion, and oncogene activation. Cardiovascular (CV) disease is a major driver of GDF-15 production. GDF-15 has favorable preanalytic characteristics and can be measured in serum and plasma by immunoassay. CONTENT: In community-dwelling individuals higher concentrations of GDF-15 are associated with increased risks of developing CV disease, chronic kidney disease, and cancer, independent of traditional CV risk Factors, renal function, and other biomarkers (C-reactive protein, B-type natriuretic peptide, cardiac troponin). Low concentrations of GDF-15 are closely associated with longevity. GDF-15 is as an independent marker of all-cause mortality and CV events in patients with coronary artery disease, and may help select patients with non–ST-elevation acute coronary syndrome for early revascularization and more intensive medical therapies. GDF-15 is independently associated with mortality and nonfatal events in atrial fibrillation and heart failure (HF) with preserved or reduced ejection fraction. GDF-15 reflects chronic disease burden and acute perturbations in HF and responds to improvements in hemodynamic status. GDF-15 is independently associated with major bleeding in patients receiving antithrombotic therapies and has been included in a new bleeding risk score, which may become useful for decision support. SUMMARY: GDF-15 captures distinct aspects of CV disease development, progression, and prognosis, which are not represented by clinical risk predictors and other biomarkers. The usefulness of GDF-15 to guide management decisions and discover new treatment targets should be further explored.
-
clinical and genetic correlates of Growth Differentiation Factor 15 in the community
Clinical Chemistry, 2012Co-Authors: Anubha Mahajan, Tibor Kempf, Minghuei Chen, Martin G Larson, Elizabeth L Mccabe, Anahita Ghorbani, Susan Cheng, Andrew D Johnson, Cecilia M Lindgren, Lars LindAbstract:BACKGROUND: Growth Differentiation Factor 15 (GDF15), a stress-responsive cytokine produced in cardiovascular cells under conditions of inflammation and oxidative stress, is emerging as an important prognostic marker in individuals with and without existing cardiovascular disease (CVD). We therefore examined the clinical and genetic correlates of circulating GDF15 concentrations, which have not been investigated collectively. METHODS: Plasma GDF15 concentrations were measured in 2991 participants in the Framingham Offspring Study who were free of clinically overt CVD (mean age, 59 years; 56% women). Clinical correlates of GDF15 were examined in multivariable analyses. We then conducted a genomewide association study of the GDF15 concentration that included participants in the Framingham Offspring Study and participants in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. RESULTS: GDF15 was positively associated with age, smoking, antihypertensive treatment, diabetes, worse kidney function, and use of nonsteroidal antiinflammatory drugs (NSAIDs), but it was negatively associated with total cholesterol and HDL cholesterol. Clinical correlates accounted for 38% of interindividual variation in the circulating GDF15 concentration, whereas genetic Factors accounted for up to 38% of the residual variability ( h 2 = 0.38; P = 2.5 × 10−11). We identified 1 locus of genomewide significance. This locus, which is on chromosome 19p13.11 and includes the GDF15 gene, is associated with GDF15 concentration (smallest P = 2.74 × 10−32 for rs888663). Conditional analyses revealed 2 independent association signals at this locus (rs888663 and rs1054564), which were associated with altered cis gene expression in blood cell lines. CONCLUSIONS: In ambulatory individuals, both cardiometabolic risk Factors and genetic Factors play important roles in determining circulating GDF15 concentrations and contribute similarly to the overall variation.
-
Growth Differentiation Factor 15 in heart failure an update
Current Heart Failure Reports, 2012Co-Authors: Kai C Wollert, Tibor KempfAbstract:Growth Differentiation Factor 15 (GDF-15) is a stress-responsive cytokine expressed in the cardiovascular system. GDF-15 is emerging as a biomarker of cardiometabolic risk and disease burden. GDF-15 integrates information from cardiac and extracardiac disease pathways that are linked to the incidence, progression, and prognosis of heart failure (HF). Increased circulating levels of GDF-15 are associated with an increased risk of developing HF in apparently healthy individuals from the community. After an acute coronary syndrome, elevated levels of GDF-15 are indicative of an increased risk of developing adverse left ventricular remodeling and HF. In patients with established HF, the levels of GDF-15 and increases in GDF-15 over time are associated with adverse outcomes. The information provided by GDF-15 is independent of established risk Factors and cardiac biomarkers, including BNP. More studies are needed to elucidate how the information provided by GDF-15 can be used for patient monitoring and formulating treatment decisions. Further understanding of the pathobiology of GDF-15 may lead to the discovery of new treatment targets in HF.
-
relations of Growth Differentiation Factor 15 to biomarkers reflecting vascular pathologies in a population based sample of elderly subjects
Scandinavian Journal of Clinical & Laboratory Investigation, 2012Co-Authors: Kai M Eggers, Tibor Kempf, Kai C Wollert, Lars Lind, Lars Wallentin, Johan Sundstrom, Agneta SiegbahnAbstract:AbstractBackground. Growth-Differentiation Factor-15 (GDF-15) has recently emerged as a risk predictor in patients with cardiac diseases. GDF-15 is commonly related to cardiovascular risk Factors, inflammatory activity and cardiac abnormalities. However, it is not clear whether it might be an indicator of vascular pathologies as well. Methods. Circulating levels of GDF-15 were measured in 1004 elderly community dwellers participating in the PIVUS study. The relations of GDF-15 to biomarkers of endothelial activation (E-selectin, P-selectin, ICAM-1, VCAM-1), extracellular matrix degradation (MMP-9, TIMP-1), coagulatory activity (D-dimer, von Willebrand Factor, prothrombin fragment 1 + 2, Factor VIIa), and fibrinolytic activity (PAI-1 activity, tPA-antigen) were assessed by multiple linear regressions. Results. The median GDF-15 level was 1135 ng/L. By linear correlation analysis, GDF-15 exhibited a moderate relation to von Willebrand Factor (r = 0.30), and weak, albeit significant relations (r = 0.13–0.29)...
-
serial measurement of Growth Differentiation Factor 15 in heart failure relation to disease severity and prognosis in the valsartan heart failure trial
Circulation, 2010Co-Authors: Inder S Anand, Tibor Kempf, Tim Allhoff, Helmut Drexler, Heike Tapken, Thomas S Rector, Franziska Jantzen, Michael A Kuskowski, Jay N Cohn, Kai C WollertAbstract:Background—Growth-Differentiation Factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure. Methods and Results—The circulating concentration of GDF-15 was measured at baseline (n=1734) and at 12 months (n=1517) in patients randomized in the Valsartan Heart Failure Trial (Val-HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (>1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; P<0.001) and first morbid event (hazard ratio, 1.020; 95% confidence interval, 1.017 to 1.023; P<0.001). In a comprehensive multiple-variable Cox regression model that included clinical prognosti...
Kai C Wollert - One of the best experts on this subject based on the ideXlab platform.
-
Growth Differentiation Factor 15 as a biomarker in cardiovascular disease
Clinical Chemistry, 2017Co-Authors: Kai C Wollert, Tibor Kempf, Lars WallentinAbstract:BACKGROUND: Growth Differentiation Factor 15 (GDF-15) is expressed and secreted in response to inflammation, oxidative stress, hypoxia, telomere erosion, and oncogene activation. Cardiovascular (CV) disease is a major driver of GDF-15 production. GDF-15 has favorable preanalytic characteristics and can be measured in serum and plasma by immunoassay. CONTENT: In community-dwelling individuals higher concentrations of GDF-15 are associated with increased risks of developing CV disease, chronic kidney disease, and cancer, independent of traditional CV risk Factors, renal function, and other biomarkers (C-reactive protein, B-type natriuretic peptide, cardiac troponin). Low concentrations of GDF-15 are closely associated with longevity. GDF-15 is as an independent marker of all-cause mortality and CV events in patients with coronary artery disease, and may help select patients with non–ST-elevation acute coronary syndrome for early revascularization and more intensive medical therapies. GDF-15 is independently associated with mortality and nonfatal events in atrial fibrillation and heart failure (HF) with preserved or reduced ejection fraction. GDF-15 reflects chronic disease burden and acute perturbations in HF and responds to improvements in hemodynamic status. GDF-15 is independently associated with major bleeding in patients receiving antithrombotic therapies and has been included in a new bleeding risk score, which may become useful for decision support. SUMMARY: GDF-15 captures distinct aspects of CV disease development, progression, and prognosis, which are not represented by clinical risk predictors and other biomarkers. The usefulness of GDF-15 to guide management decisions and discover new treatment targets should be further explored.
-
associations of circulating Growth Differentiation Factor 15 and st2 concentrations with subclinical vascular brain injury and incident stroke
Stroke, 2015Co-Authors: Kai C Wollert, Thomas J Wang, Charles Decarli, Charlotte Andersson, Sarah R Preis, Alexa S Beiser, James L JanuzziAbstract:Background and Purpose—Growth Differentiation Factor-15 (GDF-15) and soluble (s)ST2 are markers of cardiac and vascular stress. We investigated the associations between circulating concentrations of these biomarkers and incident stroke and subclinical vascular brain injury in a sample from the Framingham Offspring cohort. Methods—We followed 3374 stroke- and dementia-free individuals (mean age, 59.0±9.7 years; 53% women) attending the Framingham Offspring sixth examination cycle 11.8±3.0 years for incident stroke. A subsample of 2463 individuals underwent brain magnetic resonance imaging and neuropsychological testing ≈4.0±1.7 years after the sixth examination. Results—After adjustment for traditional cardiovascular risk Factors, B-type natriuretic peptide, high-sensitivity C-reactive protein, and urine albumin levels, higher stress biomarker levels were associated cross-sectionally with lower brain volumes (β coefficients for intracranial volume comparing fourth [Q4] versus first biomarker [Q1] quartiles...
-
Growth Differentiation Factor 15 in heart failure an update
Current Heart Failure Reports, 2012Co-Authors: Kai C Wollert, Tibor KempfAbstract:Growth Differentiation Factor 15 (GDF-15) is a stress-responsive cytokine expressed in the cardiovascular system. GDF-15 is emerging as a biomarker of cardiometabolic risk and disease burden. GDF-15 integrates information from cardiac and extracardiac disease pathways that are linked to the incidence, progression, and prognosis of heart failure (HF). Increased circulating levels of GDF-15 are associated with an increased risk of developing HF in apparently healthy individuals from the community. After an acute coronary syndrome, elevated levels of GDF-15 are indicative of an increased risk of developing adverse left ventricular remodeling and HF. In patients with established HF, the levels of GDF-15 and increases in GDF-15 over time are associated with adverse outcomes. The information provided by GDF-15 is independent of established risk Factors and cardiac biomarkers, including BNP. More studies are needed to elucidate how the information provided by GDF-15 can be used for patient monitoring and formulating treatment decisions. Further understanding of the pathobiology of GDF-15 may lead to the discovery of new treatment targets in HF.
-
relations of Growth Differentiation Factor 15 to biomarkers reflecting vascular pathologies in a population based sample of elderly subjects
Scandinavian Journal of Clinical & Laboratory Investigation, 2012Co-Authors: Kai M Eggers, Tibor Kempf, Kai C Wollert, Lars Lind, Lars Wallentin, Johan Sundstrom, Agneta SiegbahnAbstract:AbstractBackground. Growth-Differentiation Factor-15 (GDF-15) has recently emerged as a risk predictor in patients with cardiac diseases. GDF-15 is commonly related to cardiovascular risk Factors, inflammatory activity and cardiac abnormalities. However, it is not clear whether it might be an indicator of vascular pathologies as well. Methods. Circulating levels of GDF-15 were measured in 1004 elderly community dwellers participating in the PIVUS study. The relations of GDF-15 to biomarkers of endothelial activation (E-selectin, P-selectin, ICAM-1, VCAM-1), extracellular matrix degradation (MMP-9, TIMP-1), coagulatory activity (D-dimer, von Willebrand Factor, prothrombin fragment 1 + 2, Factor VIIa), and fibrinolytic activity (PAI-1 activity, tPA-antigen) were assessed by multiple linear regressions. Results. The median GDF-15 level was 1135 ng/L. By linear correlation analysis, GDF-15 exhibited a moderate relation to von Willebrand Factor (r = 0.30), and weak, albeit significant relations (r = 0.13–0.29)...
-
serial measurement of Growth Differentiation Factor 15 in heart failure relation to disease severity and prognosis in the valsartan heart failure trial
Circulation, 2010Co-Authors: Inder S Anand, Tibor Kempf, Tim Allhoff, Helmut Drexler, Heike Tapken, Thomas S Rector, Franziska Jantzen, Michael A Kuskowski, Jay N Cohn, Kai C WollertAbstract:Background—Growth-Differentiation Factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure. Methods and Results—The circulating concentration of GDF-15 was measured at baseline (n=1734) and at 12 months (n=1517) in patients randomized in the Valsartan Heart Failure Trial (Val-HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (>1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; P<0.001) and first morbid event (hazard ratio, 1.020; 95% confidence interval, 1.017 to 1.023; P<0.001). In a comprehensive multiple-variable Cox regression model that included clinical prognosti...
Edward Seto - One of the best experts on this subject based on the ideXlab platform.
-
activation of the Growth Differentiation Factor 11 gene by the histone deacetylase hdac inhibitor trichostatin a and repression by hdac3
Molecular and Cellular Biology, 2004Co-Authors: Xiaohong Zhang, Shihchang Tsai, Nancy Olashaw, Zhigang Yuan, Walker Wharton, Edward SetoAbstract:Histone deacetylase (HDAC) inhibitors inhibit the proliferation of transformed cells in vitro, restrain tumor Growth in animals, and are currently being actively exploited as potential anticancer agents. To identify gene targets of the HDAC inhibitor trichostatin A (TSA), we compared the gene expression profiles of BALB/c-3T3 cells treated with or without TSA. Our results show that TSA up-regulates the expression of the gene encoding Growth-Differentiation Factor 11 (Gdf11), a transforming Growth Factor β family member that inhibits cell proliferation. Detailed analyses indicated that TSA activates the gdf11 promoter through a conserved CCAAT box element. A comprehensive survey of human HDACs revealed that HDAC3 is necessary and sufficient for the repression of gdf11 promoter activity. Chromatin immunoprecipitation assays showed that treatment of cells with TSA or silencing of HDAC3 expression by small interfering RNA causes the hyperacetylation of Lys-9 in histone H3 on the gdf11 promoter. Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell Growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression.
-
activation of the Growth Differentiation Factor 11 gene by the histone deacetylase hdac inhibitor trichostatin a and repression by hdac3
Molecular and Cellular Biology, 2004Co-Authors: Xiaohong Zhang, Shihchang Tsai, Nancy Olashaw, Zhigang Yuan, Walker Wharton, Edward SetoAbstract:Histone deacetylase (HDAC) inhibitors inhibit the proliferation of transformed cells in vitro, restrain tumor Growth in animals, and are currently being actively exploited as potential anticancer agents. To identify gene targets of the HDAC inhibitor trichostatin A (TSA), we compared the gene expression profiles of BALB/c-3T3 cells treated with or without TSA. Our results show that TSA up-regulates the expression of the gene encoding Growth-Differentiation Factor 11 (Gdf11), a transforming Growth Factor beta family member that inhibits cell proliferation. Detailed analyses indicated that TSA activates the gdf11 promoter through a conserved CCAAT box element. A comprehensive survey of human HDACs revealed that HDAC3 is necessary and sufficient for the repression of gdf11 promoter activity. Chromatin immunoprecipitation assays showed that treatment of cells with TSA or silencing of HDAC3 expression by small interfering RNA causes the hyperacetylation of Lys-9 in histone H3 on the gdf11 promoter. Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell Growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression.
Sejin Lee - One of the best experts on this subject based on the ideXlab platform.
-
redundancy of myostatin and Growth Differentiation Factor 11 function
BMC Developmental Biology, 2009Co-Authors: Alexandra C Mcpherron, Thanh V Huynh, Sejin LeeAbstract:Background Myostatin (Mstn) and Growth/Differentiation Factor 11 (Gdf11) are highly related transforming Growth Factor β (TGFβ) family members that play important roles in regulating embryonic development and adult tissue homeostasis. Despite their high degree of sequence identity, targeted mutations in these genes result in non-overlapping phenotypes affecting distinct biological processes. Loss of Mstn in mice causes a doubling of skeletal muscle mass while loss of Gdf11 in mice causes dramatic anterior homeotic transformations of the axial skeleton, kidney agenesis, and an increase in progenitor cell number in several tissues. In order to investigate the possible functional redundancy of myostatin and Gdf11, we analyzed the effect of eliminating the functions of both of these signaling molecules.
-
characterization of Growth Differentiation Factor 15 a transforming Growth Factor β superfamily member induced following liver injury
Molecular and Cellular Biology, 2000Co-Authors: Edward C Hsiao, Thanh V Huynh, Leonidas G Koniaris, Teresa Zimmerskoniaris, Suzanne Sebald, Sejin LeeAbstract:We have identified a new murine transforming Growth Factor beta superfamily member, Growth-Differentiation Factor 15 (Gdf15), that is expressed at highest levels in adult liver. As determined by Northern analysis, the expression of Gdf15 in liver was rapidly and dramatically up-regulated following various surgical and chemical treatments that cause acute liver injury and regeneration. In situ hybridization analysis revealed distinct patterns of Gdf15 mRNA localization that appeared to reflect the known patterns of hepatocyte injury in each experimental treatment. In addition, treatment of two hepatocyte-like cell lines with either carbon tetrachloride or heat shock induced Gdf15 mRNA expression, indicating that direct cellular injury can induce Gdf15 expression in the absence of other cell types, such as inflammatory cells. In order to investigate the potential functions of Gdf15, we created Gdf15 null mice by gene targeting. Homozygous null mice were viable and fertile. Despite the dramatic regulation of Gdf15 expression observed in the partial-hepatectomy and carbon tetrachloride injury models, we found no differences in the injury responses between homozygous null mutants and wild-type mice. Our findings suggest either that Gdf15 does not have a regulatory role in liver injury and regeneration or that Gdf15 function within the liver is redundant with that of other signaling molecules.
-
oocyte specific expression of Growth Differentiation Factor 9
Molecular Endocrinology, 1995Co-Authors: Sharon Mcgrath, Aurora F Esquela, Sejin LeeAbstract:Growth/Differentiation Factor-9 (GDF-9) is a previously described member of the transforming Growth Factor-beta superfamily expressed specifically in the ovary in adult mice. Using in situ hybridization methods, we have localized the expression of GDF-9 messenger RNA (mRNA) exclusively to oocytes. GDF-9 mRNA was detected in oocytes at all stages of follicular development, except in primordial follicles, in both neonatal and adult ovaries. GDF-9 mRNA continued to be expressed in oocytes after ovulation, but disappeared by 1.5 days after fertilization. Based on Western analysis of ovarian extracts using antibodies raised against recombinant GDF-9 protein, GDF-9 mRNA expressed by oocytes appears to be translated. A human homolog of GDF-9 was isolated from a complementary DNA library prepared from adult ovary mRNA. The predicted human protein is 90% identical to murine GDF-9 in the mature portion of the molecule. These results are significant because no other Growth Factor-like molecules have been shown to be...
