Growth differentiation factor-15 (GDF-15) suppresses in vitro angiogenesis through a novel interaction with connective tissue growth factor (CCN2)

2013 ◽  
Vol 114 (6) ◽  
pp. 1424-1433 ◽  
Author(s):  
Ramon J. Whitson ◽  
Marshall Scott Lucia ◽  
James R. Lambert
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
In Vitro Angiogenesis

scholarly journals Connective-Tissue Growth Factor (CTGF/CCN2) Induces Astrogenesis and Fibronectin Expression of Embryonic Neural Cells In Vitro

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0133689 ◽  
Author(s):  
Fabio A. Mendes ◽  
Juliana M. Coelho Aguiar ◽  
Suzana A. Kahn ◽  
Alice H. Reis ◽  
Luiz Gustavo Dubois ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Neural Cells ◽  
Fibronectin Expression

scholarly journals Keratinocytes Inhibit Expression of Connective Tissue Growth Factor in Fibroblasts In Vitro by an Interleukin-1α-Dependent Mechanism

2002 ◽  
Vol 119 (2) ◽  
pp. 449-455 ◽  
Author(s):  
Daniel Nowinski ◽  
Patrik Höijer ◽  
Thomas Engstrand ◽  
Bengt Gerdin ◽  
Mikael Ivarsson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Interleukin 1Α ◽  
Dependent Mechanism

scholarly journals Decorin Interacts with Connective Tissue Growth Factor (CTGF)/CCN2 by LRR12 Inhibiting Its Biological Activity

2011 ◽  
Vol 286 (27) ◽  
pp. 24242-24252 ◽  
Author(s):  
Cecilia Vial ◽  
Jaime Gutiérrez ◽  
Cristian Santander ◽  
Daniel Cabrera ◽  
Enrique Brandan
Keyword(s):  
Biological Activity ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Core Protein ◽  
Tissue Growth ◽  
Collagen Iii ◽  
Fibrotic Disorders ◽  
Leucine Rich Repeats

Fibrotic disorders are the end point of many chronic diseases in different tissues, where an accumulation of the extracellular matrix occurs, mainly because of the action of the connective tissue growth factor (CTGF/CCN2). Little is known about how this growth factor activity is regulated. We found that decorin null myoblasts are more sensitive to CTGF than wild type myoblasts, as evaluated by the accumulation of fibronectin or collagen III. Decorin added exogenously negatively regulated CTGF pro-fibrotic activity and the induction of actin stress fibers. Using co-immunoprecipitation and in vitro interaction assays, decorin and CTGF were shown to interact in a saturable manner with a Kd of 4.4 nm. This interaction requires the core protein of decorin. Experiments using the deletion mutant decorin indicated that the leucine-rich repeats (LRR) 10–12 are important for the interaction with CTGF and the negative regulation of the cytokine activity, moreover, a peptide derived from the LRR12 was able to inhibit CTGF-decorin complex formation and CTGF activity. Finally, we showed that CTGF specifically induced the synthesis of decorin, suggesting a mechanism of autoregulation. These results suggest that decorin interacts with CTGF and regulates its biological activity.

Role of Connective Tissue Growth Factor (CTGF) in Survival and Chemosensitivity of Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2593-2593
Author(s):  
Hongbo Lu ◽  
Venkata Lokesh Battula ◽  
Yuexi Shi ◽  
Richard B Lock ◽  
Suzanne Spong ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Growth Factor ◽  
Connective Tissue ◽  
Signaling Pathways ◽  
Connective Tissue Growth Factor ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Tissue Growth ◽  
Ccn Family

Abstract Abstract 2593 Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of proteins involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in 75% of acute lymphoblastic leukemia (Br J Haematol, 2007; 138(6):740–8), and that increased expression of CTGF is associated with inferior outcome in B-ALL (Blood, 2007; 109(7):3080–3). In this study, we characterized the functional role and downstream signaling pathways of CTGF in ALL cells. First, we utilized lentiviral shRNA to knock-down CTGF in RS4;11 and REH ALL cells expressing high levels of CTGF mRNA (479.3±37.2 and 57.3±5.9 copies per 100 copies of ABL1, respectively). Silencing of CTGF (CTGF-knockdown, CTGF-kd) resulted in significant suppression of leukemia cell growth (57% in RS4;11 and by 70% in REH) compared to control vector. CTGF knockdown moderately reduced adhesion of RS4;11 to fibronectin (27%±0.1%). In the in vitro culture system, CTGF knockdown significantly enhanced growth inhibition and apoptosis induction after 48 hour exposure to chemotherapy agents (annexinV(+): Vincristine 25.8±3.5%, Vincristine/CTGF-kd 42.6±2.8%; Dexamethasone 66.3±1.8%, Dexamethasone/CTGF-kd 99.3±0.6%; Methotrexate, 17.4±0.6%, Methotrexate/CTGF-kd 39.5±3.9). Analysis of signaling pathways showed that CTGF down-regulation inhibits Src phosphorylation at Tyr416. Remarkably, phosphorylation of AKT at Ser473, and of mTOR downstream targets S6 Ribosomal Protein and 4E-BP1 were significantly inhibited in CTGF-knockdown RS4;11 cells, concomitantly with upregulation of expression of AKT targets Bim and p27. No changes in the levels of apoptotic regulators cIAP1 and Bcl-xL were found. This data suggest that CTGF regulates growth and chemosensitivity of ALL cells through Src and AKT/mTOR signaling. We previously reported that an anti-CTGF monoclonal antibody significantly extended median survival of mice implanted with xenografts derived from a primary CTGF expressing ALL sample in NOD/SCID mice. We are now investigating the effects of combining anti-CTGF treatment with cytotoxic chemotherapy in this model. Blocking CTGF signaling may represent a useful adjunct to cytotoxic therapies in acute lymphoblastic leukemia. Disclosures: Spong: Fibrogen: Employment, Equity Ownership.

Effects of bone morphogenetic protein 4, gremlin, and connective tissue growth factor on estradiol and progesterone production by bovine granulosa cells

2021 ◽  
Author(s):  
L J Spicer ◽  
L F Schutz ◽  
P Y Aad
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Aromatase Activity ◽  
Large Follicle ◽  
Progesterone Production ◽  
Small Follicle

Abstract Bone morphogenetic proteins (BMP) are members of the transforming growth factor β (TGFβ) family of proteins that have been implicated in the paracrine regulation of granulosa cell (GC) function, but whether responses to BMPs change with follicular size or interact with connective tissue growth factor (CTGF) or BMP antagonists (e.g., gremlin) to directly affect GC function of cattle is unknown. Therefore, to determine the effects of BMP4 on proliferation and steroidogenesis of GC and its interaction with gremlin or CTGF, experiments were conducted using bovine GC cultures. In vitro, BMP4 (30 ng/mL) inhibited (P < 0.05) follicle-stimulating hormone (FSH) plus insulin-like growth factor 1 (IGF1)-induced progesterone and estradiol production by large- and small-follicle GC but the inhibitory effect of BMP4 on estradiol production was much more pronounced in large-follicle GC. In small-follicle GC, BMP4 had no effect (P > 0.10) on IGF1-induced proliferation, but gremlin inhibited (P < 0.05) cell proliferation and estradiol and progesterone production in IGF1 plus FSH-treated GC. In large-follicle GC, BMP4 (10-30 ng/mL) increased (P < 0.05) GC numbers and gremlin (100 ng/mL) blocked this effect. In large-follicle GC, CTGF inhibited (P < 0.05) FSH plus IGF1-induced progesterone and estradiol production, and CTGF blocked the stimulatory effect of BMP4 on GC proliferation. These results indicate that BMP4, gremlin, and CTGF inhibit GC aromatase activity and progesterone production. Also, the stimulatory effect of BMP4 on GC proliferation and the inhibitory effects of BMP4 on GC steroidogenesis are more pronounced in large versus small follicles.

scholarly journals Establishment of a recombinant expression system for connective tissue growth factor (CTGF) that models CTGF processing in utero

Reproduction ◽  
2003 ◽  
pp. 271-284 ◽  
Author(s):  
DK Ball ◽  
EE Moussad ◽  
MA Rageh ◽  
SA Kemper ◽  
DR Brigstock
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Recombinant Expression ◽  
Expression System ◽  
Limited Proteolysis ◽  
In Utero ◽  
Tissue Growth ◽  
Recombinant Expression System

Connective tissue growth factor (CTGF) stimulates cell proliferation, migration, adhesion and extracellular matrix production, and functions in processes such as development, differentiation, angiogenesis, implantation, wound healing and fibrosis. CTGF is a 38 kDa protein that comprises four discrete structural modules (modules 1-4) but is susceptible to limited proteolysis in utero yielding bioactive isoforms that comprise either modules 3 and 4 (16-20 kDa) or module 4 (10 kDa). Here we report the development of a stable cell line, termed DB1, that was generated by transfecting cDNA encoding full-length human CTGF into Chinese hamster ovary cells that were mutant for heparin sulphate and chondroitin sulphate. DB1 cells produced 38 kDa CTGF and low molecular mass CTGFs that had N-termini between modules 2 and 3 at Ala(181) (20 kDa), Leu(184) (18 kDa) or Ala(197) (16 kDa) or between modules 3 and 4 at Gly(253) (10 kDa). CTGF was exported from DB1 cells as early as 5 min after synthesis and all isoforms were readily purified from conditioned medium by sequential steps of heparin affinity, cation exchange, and reverse-phase chromatography. The 38 kDa CTGF was faithfully glycosylated and underwent limited proteolysis in the presence of thrombin, kallikrein or uterine fluids, the last of which was antagonized by anti-thrombin III. All CTGF isoforms promoted cell adhesion, mitosis and epithelial transdifferentiation in vitro as well as subcutaneous fibrosis in vivo. The establishment of this recombinant expression system allows for mass-scale production of all previously reported uterine CTGF isoforms, demonstrates that module 4 contains functional domains involved in a broad range of biological activities, and will facilitate studies of CTGF processing in vitro.

Sign in / Sign up

Export Citation Format

Share Document