Dissecting AP-1 complexity in hepatic health and disease using Genetically Modified Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE269844 | GEO | 2024/11/21
REPOSITORIES: GEO
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Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the AP-1 (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens 1 and 2 (Fra-1/2) is unknown. Here we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis and Pparg-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently directly regulated by AP-1 through a conserved distal 3’ enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the BET bromodomain inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a novel model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.
2024-04-22 | GSE261005 | GEO
Project description:Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hyphertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload. Microarrays were used to identify specific genes that might be globally affected in the absence of c-jun in cardiomyocytes. Total RNA was extracted from the hearts of 10 weeks old Junf/f (n=2) and Jun delta mu (n=2) mice using TRIzol Reagent.
2013-09-19 | E-GEOD-47898 | biostudies-arrayexpress
Project description:Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hyphertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload. Microarrays were used to identify specific genes that might be globally affected in the absence of c-jun in cardiomyocytes.
2013-09-19 | GSE47898 | GEO
Project description:The transcription factor complex AP-1 (Activator protein 1) is composed of Jun (c-Jun, JunB, JunD) and Fos proteins (c-Fos, FosB, Fra-1, Fra-2) which control a variety of stress responses, including cell proliferation, apoptosis, inflammation, wound healing, and cancer. Individual Fos proteins have been thoroughly studied in gain- and loss-of-function mouse models, which revealed important functions in bone cell proliferation and differentiation. We have recently demonstrated that loss of Fra-2 causes perinatal lethality and severe osteopenia due to several cellular defects, including a chondrocyte differentiation defect and a control of osteoclast survival and size. Moreover, we have reported a profibrogenic function of Fra-2 in transgenic mice, in which ectopic expression of Fra-2 in various organs resulted in generalized fibrosis with predominant manifestations in the lung. Fra-2 knock-out newborns have increased numbers and size of osteoclasts in vivo. The pulmonary phenotype observed in Fra-2Tg mice is characterized by vascular remodeling and obliteration of pulmonary arteries, which coincides with expression of osteopontin, an AP-1 target gene involved in vascular remodeling and fibrogenesis. These alterations are followed by inflammation; release of profibrogenic factors, such as IL-4, insulin-like growth factor 1, and CXCL5.
2011-12-01 | GSE23745 | GEO
Project description:The transcription factor complex AP-1 (Activator protein 1) is composed of Jun (c-Jun, JunB, JunD) and Fos proteins (c-Fos, FosB, Fra-1, Fra-2) which control a variety of stress responses, including cell proliferation, apoptosis, inflammation, wound healing, and cancer. Individual Fos proteins have been thoroughly studied in gain- and loss-of-function mouse models, which revealed important functions in bone cell proliferation and differentiation. We have recently demonstrated that loss of Fra-2 causes perinatal lethality and severe osteopenia due to several cellular defects, including a chondrocyte differentiation defect and a control of osteoclast survival and size. Moreover, we have reported a profibrogenic function of Fra-2 in transgenic mice, in which ectopic expression of Fra-2 in various organs resulted in generalized fibrosis with predominant manifestations in the lung. Fra-2 knock-out newborns have increased numbers and size of osteoclasts in vivo. The pulmonary phenotype observed in Fra-2Tg mice is characterized by vascular remodeling and obliteration of pulmonary arteries, which coincides with expression of osteopontin, an AP-1 target gene involved in vascular remodeling and fibrogenesis. These alterations are followed by inflammation; release of profibrogenic factors, such as IL-4, insulin-like growth factor 1, and CXCL5. The expression profiling study was performed to analyse changes in transcript levels in lung over a period of time. Total RNA of four mutant male animals at each time point (age: 6, 10 and 14 weeks) were hybridised versus a pool of total RNA of four wild type mice of the corresponding age. For each mutant animal, two technical chip hybridisations were performed, including a dye-swap experiment (in total, 8 hybridisation of each time point = 2 technical replicates x 4 biological replicates).
2011-12-01 | E-GEOD-23745 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is an aggressive clinical phenotype, and accounts for 15% to 20% of all breast cancers. The molecular determinants of malignant cell behaviors in TNBC remain largely unknown. We find that the AP-1 transcription factor component, Fra-1, is overexpressed in basal-like breast tumors, and its expression level has high prognostic significance. Depletion of Fra-1 or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes in TNBC cells. To gain insights into the transcriptional regulatory networks of AP-1 in TNBC cells, we combine genome-wide ChIP-seq with loss-of-function transcriptome analyses. We observe dysregulation of direct targets of the Fra-1/c-Jun heterodimer involved in cell proliferation, cell adhesion, and cell-cell contact. Intriguingly, we find that AP-1 mediates downregulation of E-cadherin through direct transcriptional induction of ZEB2. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and proliferative propensity. BT549 cells grown in complete medium were transfected with a control siRNA, siRNA targeting Fra-1 or siRNA targeting c-Jun for 72 h, and then global gene expression profiles were assessed. Three or four biological replicates were used for each group.
2014-06-30 | E-GEOD-46440 | biostudies-arrayexpress
Project description:Dissecting AP-1 complexity in hepatic health and disease using Genetically Modified Mice
| PRJNA1124002 | ENA
Project description:Impaired wound healing and tissue regeneration have severe consequences on the patient’s life quality. Micrograft therapies are emerging as promising and affordable alternatives to improve skin regeneration by enhancing the endogenous wound repair processes. However, the molecular mechanisms underpinning the beneficial effects of the micrograft treatments remain largely unknown. In this study, we identified the active protein-1 (AP-1) member Fos-related antigen-1 (Fra-1) to play a central role in the extracellular-signal-regulated kinase (ERK)-mediated enhanced cell migratory capacity of micrograft-treated mouse adult fibroblasts and in the human keratinocyte (HaCaT) cell model. Accordingly, we show that increased micrograft-dependent in vitro cell migration and matrix metalloprotease activity is abolished upon inhibition of AP-1. Furthermore, micrograft treatment leads to increased expression and post-translational phosphorylation of Fra-1 and c-Jun, resulting in the upregulation of wound healing associated genes mainly involved in the regulation of cell migration. Collectively, our work provides insights into the molecular mechanisms behind micrograft treatments, which might contribute to future advances in wound repair therapies.
2020-07-01 | GSE134113 | GEO
Project description:FOS, a subunit of the activator protein-1 (AP-1) transcription factor, has been implicated in various cellular changes. In the human ovary, the expression of FOS and its heterodimeric binding partners JUN, JUNB, and JUND increases in periovulatory follicles. However, the specific role of the FOS/AP-1 remains elusive. The present study determined the regulatory mechanisms driving the expression of FOS and its partners and functions of the FOS/AP-1 using primary human granulosa/lutein cells (hGLC). hCG induced a biphasic increase in the expression of FOS, peaking at 1-3h and 12h. The levels of JUN proteins were also increased by hCG, with varying expression patterns. Co-immunoprecipitation analyses revealed that FOS is present as heterodimers with all JUN proteins. hCG immediately activated PKA and p42/44MAPK signaling pathways, and inhibitors for these pathways abolished hCG-induced increases in the levels of FOS, JUN, and JUNB. To identify the genes regulated by FOS, high throughput RNA sequencing was performed using hGLC treated with hCG ± T-5224 (FOS inhibitor). Sequencing data analysis revealed that FOS inhibition affects the expression of numerous genes, including a cluster of genes involved in the periovulatory process such as matrix remodeling, prostaglandin synthesis, glycolysis/gluconeogenesis, and cholesterol biosynthesis. qPCR analysis verified hCG-induced, T-5224-regulated expression of a selection of these genes. Consistently, T-5224 attenuated hCG-induced increases in metabolic activities and cholesterol levels. This study unveiled potential downstream target genes of and a role for the FOS/AP-1 in granulosa cell metabolic changes and cholesterol biosynthesis in human periovulatory follicles.
2021-02-10 | GSE166443 | GEO
Project description:Triple negative breast cancer (TNBC) is an aggressive clinical phenotype, and accounts for 15% to 20% of all breast cancers. The molecular determinants of malignant cell behaviors in TNBC remain largely unknown. We find that the AP-1 transcription factor component, Fra-1, is overexpressed in basal-like breast tumors, and its expression level has high prognostic significance. Depletion of Fra-1 or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes in TNBC cells. To gain insights into the transcriptional regulatory networks of AP-1 in TNBC cells, we combine genome-wide ChIP-seq with loss-of-function transcriptome analyses. We observe dysregulation of direct targets of the Fra-1/c-Jun heterodimer involved in cell proliferation, cell adhesion, and cell-cell contact. Intriguingly, we find that AP-1 mediates downregulation of E-cadherin through direct transcriptional induction of ZEB2. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and proliferative propensity.
2014-06-30 | GSE46440 | GEO