Browsing by Subject "GROWTH-FACTOR-BETA"

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  • Rodriguez-Barrueco, Ruth; Latorre, Jessica; Devis-Jauregui, Laura; Lluch, Aina; Bonifaci, Nuria; Llobet, Francisco J.; Olivan, Mireia; Coll-Iglesias, Laura; Gassner, Katja; Davis, Meredith L.; Moreno-Navarrete, Jose M.; Castells-Nobau, Anna; Plata-Pena, Laura; Dalmau-Pastor, Miki; Horing, Marcus; Liebisch, Gerhard; Olkkonen, Vesa M.; Arnoriaga-Rodriguez, Maria; Ricart, Wifredo; Fernandez-Real, Jose M.; Silva, Jose M.; Ortega, Francisco J.; Llobet-Navas, David (2022)
    The H19X-encoded miR-424(322)/503 cluster regulates multiple cellular functions. Here, it is reported for the first time that it is also a critical linchpin of fat mass expansion. Deletion of this miRNA cluster in mice results in obesity, while increasing the pool of early adipocyte progenitors and hypertrophied adipocytes. Complementary loss and gain of function experiments and RNA sequencing demonstrate that miR-424(322)/503 regulates a conserved genetic program involved in the differentiation and commitment of white adipocytes. Mechanistically, it is demonstrated that miR-424(322)/503 targets gamma-Synuclein (SNCG), a factor that mediates this program rearrangement by controlling metabolic functions in fat cells, allowing adipocyte differentiation and adipose tissue enlargement. Accordingly, diminished miR-424(322) in mice and obese humans co-segregate with increased SNCG in fat and peripheral blood as mutually exclusive features of obesity, being normalized upon weight loss. The data unveil a previously unknown regulatory mechanism offat mass expansion tightly controlled by the miR-424(322)/503 through SNCG.
  • Aula, Hanna; Skyttä, Tanja; Tuohinen, Suvi; Luukkaala, Tiina; Hämäläinen, Mari; Virtanen, Vesa; Raatikainen, Pekka; Moilanen, Eeva; Kellokumpu-Lehtinen, Pirkko-Liisa (2018)
    BackgroundRadiation-induced heart disease is mainly caused by activation of the fibrotic process. Transforming growth factor-beta 1 (TGF-1) and platelet-derived growth factor (PDGF) are pro-fibrotic mediators. The aim of our study was to evaluate the behavior of TGF-1 and PDGF during adjuvant radiotherapy (RT) for breast cancer and the association of these cytokines with echocardiographic changes.MethodsOur study included 73 women with early-stage breast cancer or ductal carcinoma in situ (DCIS) receiving post-operative RT but not chemotherapy. TGF-1 and PDGF levels in serum samples taken before and on the last day of RT were measured by an enzyme-linked immunosorbent assay. Echocardiography was also performed at same time points. Patients were grouped according to a15% worsening in tricuspid annular plane systolic excursion (TAPSE) and pericardium calibrated integrated backscatter (cIBS).ResultsIn all patients, the median TGF-1 decreased from 25.0 (IQR 21.1-30.3) ng/ml to 23.6 (IQR 19.6-26.8) ng/ml (p=0.003), and the median PDGF decreased from 18.0 (IQR 13.7-22.7) ng/ml to 15.6 (IQR 12.7-19.5) ng/ml (p
  • Panahi, Mahmod; Mesri, Naeimeh Yousefi; Samuelsson, Eva-Britt; Coupland, Kirsten G.; Forsell, Charlotte; Graff, Caroline; Tikka, Saara; Winblad, Bengt; Viitanen, Matti; Karlström, Helena; Sundström, Erik; Behbahani, Homira (2018)
    Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial fatal progressive degenerative disorder. One of the pathological hallmarks of CADASIL is a dramatic reduction of vascular smooth muscle cells (VSMCs) in cerebral arteries. Using VSMCs from the vasculature of the human umbilical cord, placenta and cerebrum of CADASIL patients, we found that CADASIL VSMCs had a lower proliferation rate compared to control VSMCs. Exposure of control VSMCs and endothelial cells (ECs) to media derived from CADASIL VSMCs lowered the proliferation rate of all cells examined. By quantitative RT-PCR analysis, we observed increased Transforming growth factor-beta (TGF beta) gene expression in CADASIL VSMCs. Adding TGF beta-neutralizing antibody restored the proliferation rate of CADASIL VSMCs. We assessed proliferation differences in the presence or absence of TGF beta-neutralizing antibody in ECs co-cultured with VSMCs. ECs co-cultured with CADASIL VSMCs exhibited a lower proliferation rate than those co-cultured with control VSMCs, and neutralization of TGF beta normalized the proliferation rate of ECs co-cultured with CADASIL VSMCs. We suggest that increased TGF beta expression in CADASIL VSMCs is involved in the reduced VSMC proliferation in CADASIL and may play a role in situ in altered proliferation of neighbouring cells in the vasculature.
  • Voutilainen, Silja H.; Kosola, Silja K.; Lohi, Jouko; Jahnukainen, Timo; Pakarinen, Mikko P.; Jalanko, Hannu J (2021)
    Background Unexplained graft fibrosis and inflammation are common after pediatric liver transplantation (LT). Objective We investigated the graft expression of fibrogenic genes and correlated the findings with transplant histopathology and outcome. Methods Liver biopsies from 29 recipients were obtained at a median of 13.1 (IQR: 5.0-18.4) years after pediatric LT. Control samples were from six liver-healthy subjects. Hepatic expression of 40 fibrosis-related genes was correlated to histological findings: normal histology, fibrosis with no inflammation, and fibrosis with inflammation. Liver function was evaluated after a subsequent follow-up of 9.0 years (IQR: 8.0-9.4). Results Patients with fibrosis and no inflammation had significantly increased gene expression of profibrotic TGF-beta 3 (1.17 vs. 1.02 p = .005), CTGF (1.64 vs. 0.66 p = .014), PDGF-alpha (1.79 vs. 0.98 p = .049), PDGF -beta (0.99 vs. 0.76 p = .006), integrin-subunit-beta 1 (1.19 vs. 1.02 p = .045), alpha-SMA (1.12 vs. 0.58 p = .013), type I collagen (0.82 vs. 0.53 p = .005) and antifibrotic decorin (1.15 vs. 0.99 p = .045) compared to patients with normal histology. mRNA expression of VEGF A (0.84 vs. 1.06 p = .049) was lower. Only a few of the studied genes were upregulated in patients with both fibrosis and inflammation. The gene expression levels showed no association with later graft outcome. Conclusions Altered hepatic expression of fibrosis-related genes is associated with graft fibrosis without concurrent inflammation.
  • Belitskin, Denis; Pant, Shishir M.; Munne, Pauliina; Suleymanova, Ilida; Belitskina, Kati; Ala-Hongisto, Hanna; Englund, Johanna; Raatikainen, Tiina; Klezovitch, Olga; Vasioukhin, Valeri; Li, Shuo; Wu, Qingyu; Monni, Outi; Kuure, Satu; Laakkonen, Pirjo; Pouwels, Jeroen; Tervonen, Topi A.; Klefström, Juha (2021)
    Transforming growth factor-beta (TGF beta) is a multifunctional cytokine with a well-established role in mammary gland development and both oncogenic and tumor-suppressive functions. The extracellular matrix (ECM) indirectly regulates TGF beta activity by acting as a storage compartment of latent-TGF beta, but how TGF beta is released from the ECM via proteolytic mechanisms remains largely unknown. In this study, we demonstrate that hepsin, a type II transmembrane protease overexpressed in 70% of breast tumors, promotes canonical TGF beta signaling through the release of latent-TGF beta from the ECM storage compartment. Mammary glands in hepsin CRISPR knockout mice showed reduced TGF beta signaling and increased epithelial branching, accompanied by increased levels of fibronectin and latent-TGF beta 1, while overexpression of hepsin in mammary tumors increased TGF beta signaling. Cell-free and cell-based experiments showed that hepsin is capable of direct proteolytic cleavage of fibronectin but not latent-TGF beta and, importantly, that the ability of hepsin to activate TGF beta signaling is dependent on fibronectin. Altogether, this study demonstrates a role for hepsin as a regulator of the TGF beta pathway in the mammary gland via a novel mechanism involving proteolytic downmodulation of fibronectin.
  • Kovac, Bianca; Makela, Tomi P.; Vallenius, Tea (2018)
    The controlled formation and stabilization of E-cadherin-based adhesions is vital for epithelial integrity. This requires co-operation between the E-cadherin-based adhesions and the associated actin cytoskeleton. In cancer, this co-operation often fails, predisposing cells to migration through molecular mechanisms that have only been partially characterized. Here, we demonstrate that the actin filament cross-linker alpha-actinin-1 is frequently increased in human breast cancer. In mammary epithelial cells, the increased alpha-actinin-1 levels promote cell migration and induce disorganized acini-like structures in Matrigel. This is accompanied by a major reorganization of the actin cytoskeleton and the associated E-cadherin-based adhesions. Increased expression of alpha-actinin-1 is particularly noted in basal-like breast cancer cell lines, and in breast cancer patients it associates with poor prognosis in basal-like subtypes. Downregulation of alpha-actinin-1 in E-cadherin expressing basal-like breast cancer cells demonstrate that alpha-actinin-1-assembled actin fibers destabilize E-cadherin-based adhesions. Taken together, these results indicate that increased alpha-actinin-1 expression destabilizes E-cadherin-based adhesions, which is likely to promote the migratory potential of breast cancer cells. Furthermore, our results identify alpha-actinin-1 as a candidate prognostic biomarker in basal-like breast cancer.
  • Tomasovic, Ana; Kurrle, Nina; Wempe, Frank; De-Zolt, Siike; Scheibe, Susan; Koli, Katri; Serchinger, Martin; Schnuetgen, Frank; Sueruen, Duran; Sterner-Kock, Anja; Weissmann, Norbert; von Meichner, Harald (2017)
    Latent transforming growth factor beta binding protein 4 (LTBP4) belongs to the fibrillin/LTBP family of proteins and plays an important role as a structural component of extracellular matrix (ECM) and local regulator of TGF beta signaling. We have previously reported that Ltbp4S knock out mice (Ltbp4S-/-) develop centrilobular emphysema reminiscent of late stage COPD, which could be partially rescued by inactivating the antioxidant protein Sestrin 2 (Sesn2). More recent studies showed that Sesn2 knock out mice upregulate Pdgfr beta-controlled alveolar maintenance programs that protect against cigarette smoke induced pulmonary emphysema. Based on this, we hypothesized that the emphysema of Ltbp4S-/- mice is primarily caused by defective Pdgfr beta signaling. Here we show that LTBP4 induces Pdgfr beta signaling by inhibiting the antioxidant Nr12/Keap1 pathway in a TGF beta-dependent manner. Overall, our data identified Ltbp4 as a major player in lung remodeling and injury repair. (C) 2016 The Authors. Published by Elsevier B.V.
  • Datta, Neeta; Lindfors, Sonja; Miura, Naoyuki; Saleem, Moin A.; Lehtonen, Sanna (2016)
    Obesity and diabetes-related kidney diseases associate with renal failure and cardiovascular morbidity, and represent a major health issue worldwide. However, the molecular mechanisms leading to their development remain poorly understood. We observed increased expression of transcription factor FoxC2 in the podocytes of obese Zucker rats that are insulin resistant and albuminuric. We also found that depletion of adiponectin, an adipocyte-derived hormone whose secretion is decreased in obesity, up regulated FOXC2 in differentiated human podocytes in vitro. Overexpression of FOXC2 in cultured human podocytes led to increased nuclear expression of FOXC2 associated with a change of cellular morphology. This was accompanied by upregulation of vimentin, a key mesenchymal marker, and active beta-catenin, associated with podocyte injury. We also observed re-organization of the actin cytoskeleton, disrupted localization of the tight junction protein ZO-1, and increased motility of podocytes overexpressing FOXC2. These data indicate that the expression of FOXC2 in podocytes needs to be tightly regulated, and that its overexpression induces a chain of cellular events leading to podocyte dysfunction. These changes may lead to podocyte detachment and depletion ultimately contributing to albuminuria. We also suggest a novel molecular mechanism linking obesity-induced decrease in adiponectin to podocyte dysfunction via upregulation of FOXC2. (C) 2015 Elsevier Inc. All rights reserved.
  • Amankwah, Ernest K.; Wang, Qinggang; Schildkraut, Joellen M.; Tsai, Ya-Yu; Ramus, Susan J.; Fridley, Brooke L.; Beesley, Jonathan; Johnatty, Sharon E.; Webb, Penelope M.; Chenevix-Trench, Georgia; Dale, Laura C.; Lambrechts, Diether; Amant, Frederic; Despierre, Evelyn; Vergote, Ignace; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Menon, Usha; Chang-Claude, Jenny; Wang-Gohrke, Shan; Anton-Culver, Hoda; Ziogas, Argyrios; Doerk, Thilo; Duerst, Matthias; Antonenkova, Natalia; Bogdanova, Natalia; Brown, Robert; Flanagan, James M.; Kaye, Stanley B.; Paul, James; Butzow, Ralf; Nevanlinna, Heli; Campbell, Ian; Eccles, Diana M.; Karlan, Beth Y.; Gross, Jenny; Walsh, Christine; Pharoah, Paul D. P.; Song, Honglin; Kjaer, Susanne Kruger; Hogdall, Estrid; Hogdall, Claus; Lundvall, Lene; Nedergaard, Lotte; Kiemeney, Lambertus A. L. M.; Massuger, Leon F. A. G.; van Altena, Anne M.; Vermeulen, Sita H. H. M.; Le, Nhu D.; Brooks-Wilson, Angela; Australian Ovarian Canc Study Grp (2011)
  • Roussa, Eleni; Speer, Jan Manuel; Chudotvorova, Ilona; Khakipoor, Shokoufeh; Smirnov, Sergei; Rivera Baeza, Claudio; Krieglstein, Kerstin (2016)
    Functional activation of the neuronal K+-Cl- co-transporter KCC2 (also known as SLC12A5) is a prerequisite for shifting GABAA responses from depolarizing to hyperpolarizing during development. Here, we introduce transforming growth factor beta 2 (TGF-beta 2) as a new regulator of KCC2 membrane trafficking and functional activation. TGF-beta 2 controls membrane trafficking, surface expression and activity of KCC2 in developing and mature mouse primary hippocampal neurons, as determined by immunoblotting, immunofluorescence, biotinylation of surface proteins and KCC2-mediated Cl- extrusion. We also identify the signaling pathway from TGF-beta 2 to cAMP-response-element-binding protein (CREB) and Ras-associated binding protein 11b (Rab11b) as the underlying mechanism for TGF-beta 2-mediated KCC2 trafficking and functional activation. TGF-beta 2 increases colocalization and interaction of KCC2 with Rab11b, as determined by 3D stimulated emission depletion (STED) microscopy and co-immunoprecipitation, respectively, induces CREB phosphorylation, and enhances Rab11b gene expression. Loss of function of either CREB1 or Rab11b suppressed TGF-beta 2-dependent KCC2 trafficking, surface expression and functionality. Thus, TGF-beta 2 is a new regulatory factor for KCC2 functional activation and membrane trafficking, and a putative indispensable molecular determinant for the developmental shift of GABAergic transmission.
  • Anthoni, M.; Fyhrquist-Vanni, N.; Wolff, H.; Alenius, H.; Lauerma, A. (2008)
    Background Transforming growth factor (TGF)-beta is an important modulator of immune functions and cellular responses, such as differentiation, proliferation, migration and apoptosis. The Smad proteins, which are intracellular TGF-beta signal transducers, mediate most actions of TGF-beta. Objectives This study examines the role of Smad3 in a murine model of contact hypersensitivity (CHS). Methods The CHS response to oxazolone was studied in Smad3-deficient mice. The ear swelling response was measured and skin biopsies from oxazolone-sensitized skin areas were obtained for RNA isolation, immunohistochemical analyses and histology. Ear draining lymph nodes were collected for RNA isolation and proliferation tests. Quantitative real-time polymerase chain reaction was used to quantify mRNA expression of cytokines, chemokines and transcription factors. Results The expression of proinflammatory [interleukin (IL)-1 beta, tumour necrosis factor-alpha, IL-6], Th2 (IL-4) and Th17 type cytokines (IL-17), as well as regulatory components (TGF-beta, Foxp3) increased significantly at the mRNA level in the skin of oxazolone-treated Smad3-/- mice when compared with wild-type controls. The expression of the Th1 type cytokine IFN-gamma and the chemokines CXCL9 and CXCL10 was, however, unaffected by the lack of Smad3. The number of neutrophils and expression of the chemokines CCL3 and CXCL5, which are both involved in neutrophil recruitment, were increased in mice lacking Smad3. Also Th2 type chemokines CCL24, CCL3 and CXCL5 were increased in the skin of Smad3-/- mice compared with wild-type mice. In the lymph nodes, mRNA of IL-1 beta and IL-17, but not IL-4, TGF-beta or Foxp3, was increased in Smad3-/- mice during the CHS response. Conclusions The lack of intact TGF-beta signalling via Smad3 results in an increased proinflammatory, Th2 and Th17 type response in the skin, as well as increased expression of regulatory elements such as TGF-beta and Foxp3. Understanding the role of Smad3 in the CHS response may offer treatment and prevention strategies in this often disabling disease.
  • Kelloniemi, Annina; Aro, Jani; Näpänkangas, Juha; Koivisto, Elina; Mustonen, Erja; Ruskoaho, Heikki; Rysä, Jaana (2015)
    Background: The transforming growth factor (TGF)-beta is one of the key mediators in cardiac remodelling occurring after myocardial infarction (MI) and in hypertensive heart disease. The TGF-beta-stimulated clone 22 (TSC-22) is a leucine zipper protein expressed in many tissues and possessing various transcription-modulating activities. However, its function in the heart remains unknown. Methods: The aim of the present study was to characterize cardiac TSC-22 expression in vivo in cardiac remodelling and in myocytes in vitro. In addition, we used TSC-22 gene transfer in order to examine the effects of TSC-22 on cardiac gene expression and function. Results: We found that TSC-22 is rapidly up-regulated by multiple hypertrophic stimuli, and in post-MI remodelling both TSC-22 mRNA and protein levels were up-regulated (4.1-fold, P <0.001 and 3.0-fold, P <0.05, respectively) already on day 1. We observed that both losartan and metoprolol treatments reduced left ventricular TSC-22 gene expression. Finally, TSC-22 overexpression by local intramyocardial adenovirus-mediated gene delivery showed that TSC-22 appears to have a role in regulating collagen type III alpha 1 gene expression in the heart. Conclusions: These results demonstrate that TSC-22 expression is induced in response to cardiac overload. Moreover, our data suggests that, by regulating collagen expression in the heart in vivo, TSC-22 could be a potential target for fibrosis-preventing therapies.