CCN5: biology and pathophysiology.
Ontology highlight
ABSTRACT:
SUBMITTER: Russo JW
PROVIDER: S-EPMC2948116 | biostudies-other | 2010 Oct
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.
| S-EPMC6903413 | biostudies-literature
Project description:Eukaryotic proteomes are enormously sophisticated through versatile post-translational modifications (PTMs) of proteins. A large variety of code generated via PTMs of proteins by ubiquitin (ubiquitination) and ubiquitin-like proteins (Ubls), such as interferon (IFN)-stimulated gene 15 (ISG15), small ubiquitin-related modifier (SUMO) and neural precursor cell expressed, developmentally downregulated 8 (NEDD8), not only provides distinct signals but also orchestrates a plethora of biological processes, thereby underscoring the necessity for sophisticated and fine-tuned mechanisms of code regulation. Deubiquitinases (DUBs) play a pivotal role in the disassembly of the complex code and removal of the signal. Ubiquitin-specific protease 18 (USP18), originally referred to as UBP43, is a major DUB that reverses the PTM of target proteins by ISG15 (ISGylation). Intriguingly, USP18 is a multifaceted protein that not only removes ISG15 or ubiquitin from conjugated proteins in a deconjugating activity-dependent manner but also acts as a negative modulator of type I IFN signaling, irrespective of its catalytic activity. The function of USP18 has become gradually clear, but not yet been completely addressed. In this review, we summarize recent advances in our understanding of the multifaceted roles of USP18. We also highlight new insights into how USP18 is implicated not only in physiology but also in pathogenesis of various human diseases, involving infectious diseases, neurological disorders, and cancers. Eventually, we integrate a discussion of the potential of therapeutic interventions for targeting USP18 for disease treatment.
| S-EPMC7555095 | biostudies-literature
Project description:BACKGROUND:Cardiac fibrosis (CF) is associated with increased ventricular stiffness and diastolic dysfunction and is an independent predictor of long-term clinical outcomes of patients with heart failure (HF). We previously showed that the matricellular CCN5 protein is cardioprotective via its ability to inhibit CF and preserve cardiac contractility. OBJECTIVES:This study examined the role of CCN5 in human heart failure and tested whether CCN5 can reverse established CF in an experimental model of HF induced by pressure overload. METHODS:Human hearts were obtained from patients with end-stage heart failure. Extensive CF was induced by applying transverse aortic constriction for 8 weeks, which was followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight weeks following gene transfer, cellular and molecular effects were examined. RESULTS:Expression of CCN5 was significantly decreased in failing hearts from patients with end-stage heart failure compared to nonfailing hearts. Trichrome staining and myofibroblast content measurements revealed that the established CF had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated with inhibition of the transforming growth factor beta signaling pathway. CCN5 significantly inhibited endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical processes for CF progression, both in vivo and in vitro. In addition, CCN5 induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts, both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway specifically in myofibroblasts, which may have been due the ability of CCN5 to inhibit the activity of NF?B, an antiapoptotic molecule. CONCLUSIONS:CCN5 can reverse established CF by inhibiting the generation of and enhancing apoptosis of myofibroblasts in the myocardium. CCN5 may provide a novel platform for the development of targeted anti-CF therapies.
| S-EPMC5887128 | biostudies-literature
Project description:CCN5 is a member of the CCN (Connective Tissue Growth Factor/Cysteine-rich 61/Nephroblastoma overexpressed) family and was identified as an estrogen-inducible gene in estrogen receptor-positive cell lines. However, the role of CCN5 in breast carcinogenesis remains unclear. We report here that CCN5 protein is localized mostly in the cytoplasm, and in part in the nucleus, of human tumor breast tissue. Using a heterologous transcription assay, we demonstrate that CCN5 can act as a transcriptional repressor, presumably through association with histone deacetylase HDAC1. Microarray gene expression analysis showed that CCN5 represses expression of genes associated with epithelial-mesenchymal transition (EMT) as well as expression of key components of the TGF-beta signaling pathway, prominent among them TGF-betaRII receptor. We show that CCN5 is recruited to the TGF-betaRII promoter, thereby providing a mechanism by which CCN5 restricts transcription of the TGF-betaRII gene. Consistent with this finding, we found that CCN5 functions to suppress TGF-beta-induced transcriptional responses and invasion that is concomitant with EMT. Thus, our data uncovered CCN5 as a novel transcriptional repressor that plays an important role in regulating tumor progression functioning, at least in part, by inhibiting the expression of genes involved in the TGF-beta signaling cascade that is known to promote EMT.
2011-11-30 | GSE25431 | GEO
Project description:Sickle cell disease has been very well characterized as a single amino acid molecular disorder of hemoglobin leading to its pathological polymerization, with resulting red cell rigidity that causes poor microvascular blood flow, with consequent tissue ischemia and infarction. More recently, an independent spectrum of pathophysiology of blood vessel function has been demonstrated, involving abnormal vascular tone and activated, adhesive endothelium. These vasculopathic abnormalities are attributable to pathways involving hemolysis-associated defects in nitric oxide bioavailability, oxidative stress, ischemia-reperfusion injury, hemostatic activation, leukocytes and platelets. Vasculopathy of sickle cell disease has been implicated in the development of pulmonary hypertension, stroke, leg ulceration and priapism, particularly associated with hemolytic severity, and reported also in other severe hemolytic disorders. This vasculopathy might also play a role in other chronic organ dysfunction in patients with sickle cell disease. These pathways present novel targets for pharmacologic intervention, and several clinical trials are already under way. The authors present their perspectives of a workshop held at the National Institutes of Health in August 2008 on vasculopathy in sickle cell disease, along with meritorious future scientific questions on the topic of vascular complications of sickle cell disease.
| S-EPMC3209715 | biostudies-literature
Project description:CCN5 is a member of the CCN (Connective Tissue Growth Factor/Cysteine-rich 61/Nephroblastoma overexpressed) family and was identified as an estrogen-inducible gene in estrogen receptor-positive cell lines. However, the role of CCN5 in breast carcinogenesis remains unclear. We report here that CCN5 protein is localized mostly in the cytoplasm, and in part in the nucleus, of human tumor breast tissue. Using a heterologous transcription assay, we demonstrate that CCN5 can act as a transcriptional repressor, presumably through association with histone deacetylase HDAC1. Microarray gene expression analysis showed that CCN5 represses expression of genes associated with epithelial-mesenchymal transition (EMT) as well as expression of key components of the TGF-beta signaling pathway, prominent among them TGF-betaRII receptor. We show that CCN5 is recruited to the TGF-betaRII promoter, thereby providing a mechanism by which CCN5 restricts transcription of the TGF-betaRII gene. Consistent with this finding, we found that CCN5 functions to suppress TGF-beta-induced transcriptional responses and invasion that is concomitant with EMT. Thus, our data uncovered CCN5 as a novel transcriptional repressor that plays an important role in regulating tumor progression functioning, at least in part, by inhibiting the expression of genes involved in the TGF-beta signaling cascade that is known to promote EMT. We performed microarray gene expression profiling of one MCF-7-sh-CCN5 sample and one MCF-7-sh-scrambled sample (control sample).
2011-11-30 | E-GEOD-25431 | biostudies-arrayexpress
Project description:CCN5 is a member of the CCN (Connective Tissue Growth Factor/Cysteine-rich 61/Nephroblastoma overexpressed) family and was identified as an estrogen-inducible gene in estrogen receptor-positive cell lines. However, the role of CCN5 in breast carcinogenesis remains unclear. We report here that CCN5 protein is localized mostly in the cytoplasm, and in part in the nucleus, of human tumor breast tissue. Using a heterologous transcription assay, we demonstrate that CCN5 can act as a transcriptional repressor, presumably through association with histone deacetylase HDAC1. Microarray gene expression analysis showed that CCN5 represses expression of genes associated with epithelial-mesenchymal transition (EMT) as well as expression of key components of the TGF-beta signaling pathway, prominent among them TGF-betaRII receptor. We show that CCN5 is recruited to the TGF-betaRII promoter, thereby providing a mechanism by which CCN5 restricts transcription of the TGF-betaRII gene. Consistent with this finding, we found that CCN5 functions to suppress TGF-beta-induced transcriptional responses and invasion that is concomitant with EMT. Thus, our data uncovered CCN5 as a novel transcriptional repressor that plays an important role in regulating tumor progression functioning, at least in part, by inhibiting the expression of genes involved in the TGF-beta signaling cascade that is known to promote EMT. We performed microarray gene expression profiling of one MCF-7-sh-CCN5 sample and one MCF-7-sh-scrambled sample (control sample).
| S-ECPF-GEOD-25431 | biostudies-other
Project description:For nearly a century, the human heart has been viewed as a terminally differentiated postmitotic organ in which the number of cardiomyocytes is established at birth, and these cells persist throughout the lifespan of the organ and organism. However, the discovery that cardiac stem cells live in the heart and differentiate into the various cardiac cell lineages has changed profoundly our understanding of myocardial biology. Cardiac stem cells regulate myocyte turnover and condition myocardial recovery after injury. This novel information imposes a reconsideration of the mechanisms involved in myocardial aging and the progression of cardiac hypertrophy to heart failure. Similarly, the processes implicated in the adaptation of the infarcted heart have to be dissected in terms of the critical role that cardiac stem cells and myocyte regeneration play in the restoration of myocardial mass and ventricular function. Several categories of cardiac progenitors have been described but, thus far, the c-kit-positive cell is the only class of resident cells with the biological and functional properties of tissue specific adult stem cells.
| S-EPMC3299091 | biostudies-literature
Project description:Ligamentum flavum hypertrophy (LFH) is the most important component of lumbar spinal canal stenosis. Although the pathophysiology of LFH has been extensively studied, no method has been proposed to prevent or treat it. Since the transforming growth factor-? (TGF-?) pathway is known to be critical in LFH pathology, we investigated whether LFH could be prevented by blocking or modulating the TGF-? mechanism. Human LF cells were used for the experiments. First, we created TGF-? receptor 1 (TGFBR1) knock out (KO) cells with CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 biotechnology and treated them with TGF-?1 to determine the effects of blocking the TGF-? pathway. Subsequently, we studied the effect of CCN5, which has recently been proposed to modulate the TGF-? pathway. To assess the predisposition toward fibrosis, ?-smooth muscle actin (?SMA), fibronectin, collagen-1, collagen-3, and CCN2 were evaluated with quantitative real-time polymerase chain reaction, western blotting, and immunocytochemistry. The TGFBR1 KO LF cells were successfully constructed with high KO efficiency. In wild-type (WT) cells, treatment with TGF-?1 resulted in the overexpression of the messenger RNA (mRNA) of fibrosis-related factors. However, in KO cells, the responses to TGF-?1 stimulation were significantly lower. In addition, CCN5 and TGF-?1 co-treatment caused a notable reduction in mRNA expression levels compared with TGF-?1 stimulation only. The ?SMA protein expression increased with TGF-?1 but decreased with CCN5 treatment. TGF-?1 induced LF cell transdifferentiation from fibroblasts to myofibroblasts. However, this cell transition dramatically decreased in the presence of CCN5. In conclusion, CCN5 could prevent LFH by modulating the TGF-? pathway. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2634-2644, 2019.
| S-EPMC6899892 | biostudies-literature
Project description:Overweight and obesity before conception as well as excessive weight gain during pregnancy are associated with endocrinological changes of mother and fetus. Insulin resistance physiologically increases during pregnancy, additional obesity further increases insulin resistance. In combination with reduced insulin secretion this leads to gestational diabetes which may develop into type-2-diabetes. The adipose tissue produces TNF-alpha, interleukins and leptin and upregulates these adipokines. Insulin resistance and obesity induce inflammatory processes and vascular dysfunction, which explains the increased rate of pregnancy-related hypertension and pre-eclampsia in obese pregnant women. Between 14 and 28 gestational weeks, the fetal adipose tissue is generated and the number of fat lobules is determined. Thereafter, an increase in adipose tissue is arranged by an enlargement of the lobules (hypertrophy), or even an increase in the number of fat cells (hyperplasia). Human and animal studies have shown that maternal obesity "programmes" the offspring for further obesity and chronic disease. Pregnant women, midwives, physicians and health care politicians should be better informed about prevention, pathophysiological mechanisms, and the burden for society caused by obesity before, during and after pregnancy.
| S-EPMC4119104 | biostudies-literature