Lumican is down-regulated in cells expressing endoglin. Evidence for an inverse correlationship between Endoglin and Lumican expression

Botella, Luisa María; Sanz-Rodrı́guez, Francisco; Sánchez-Elsner, Tilman; Langa, Carmen; Ramírez, José Ramón; Vary, Calvin P.H.; Roughley, Peter J.; Bernabéu, Carmelo

doi:10.1016/j.matbio.2003.11.006

Cited by 15 publications

(7 citation statements)

References 49 publications

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“…Previous studies have reported that endoglin overexpression reduces other biological effects of TGF-β1 [7,9,29]. The classical mechanism of cell signaling by TGF-β is the activation of the Smad cascade [32]. The mechanism that we show here is an additional one, involving regulation of MAP kinase activation by endoglin.…”

Section: Discussionsupporting

confidence: 56%

Endoglin Modulation of TGF-ß1-Induced Collagen Synthesis is Dependent on ERK1/2 MAPK Activation

Rodríguez-Barbero¹,

Obreo²,

Alvarez-Muñoz³

et al. 2006

Cell Physiol Biochem

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Background/Aims: Transforming growth factor-β1 (TGF-β1) plays a pivotal role in the extracellular matrix accumulation observed in fibrotic diseases. Endoglin is an important component of the TGF-β receptor complex highly expressed in tissues undergoing fibrotic processes. Endoglin expression regulates the effect of TGF-β on extracellular matrix synthesis. The purpose of our study has been to understand the molecular mechanism by which endoglin exerts its effects on fibrosis and the possible role of MAP kinases in these effects. Methods: We have assessed in mock and in endoglin-transfected L6E9 myoblasts the effect of TGF-β1 on collagen mRNA by Northern blot and effect of TGF-β1 on collagen content in the cultured medium by [³H]-Proline incorporation into collagen proteins. Total and activated MAPK and their role on collagen synthesis were assessed by Western blot. Results: TGF-β1 induced an increase on α₂ (I) collagen mRNA expression and collagen accumulation in mock-transfected myoblasts, whereas the response was much lower in endoglintransfected cells. TGF-β1 activated the ERK1/2 and p38 MAPK pathways but not the JNK pathway in L6E9 myoblasts. TGF-β1-induced α₂ (I) collagen mRNA expression and collagen accumulation were completely inhibited by SB203580, in either mock or endoglintransfected myoblasts. PD98059 increased TGF-β1 induced-collagen synthesis and accumulation in endoglin-transfected myoblasts but not in mock cells. Conclusion: Our studies demonstrate that TGF-β1- induced collagen synthesis is mediated by p38 MAPK activation in L6E9 myoblasts. Furthermore, endoglin expression reduces basal and TGF-β1 induced collagen synthesis when ERK1/2 pathway is operating.

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Section: Discussionsupporting

confidence: 56%

Endoglin Modulation of TGF-ß1-Induced Collagen Synthesis is Dependent on ERK1/2 MAPK Activation

Rodríguez-Barbero¹,

Obreo²,

Alvarez-Muñoz³

et al. 2006

Cell Physiol Biochem

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“…Recent reports of endothelial cells plated on lumican reveals reduced pseudotube formation [17] and previous research on tubulating endothelial cells has demonstrated expression of lumican increases during the resolution phase of angiogenesis in which vascularization ceases and the vessel returns to a state of angiostasis [21]. This angiostatic state can be observed in large resting vessels where expression of lumican is high [22].…”

Section: Discussionmentioning

confidence: 94%

“…Functionally, endothelial cell expression of lumican increases during the resolution phase of angiogenesis in which vascularization ceases and the vessel returns to a state of angiostasis [21]. Additionally, lumican is inversely regulated with endoglin, a marker for angiogenic tissue [22]. Not surprisingly, lum -/-fmod -/-knockout mice exhibit increased vascularization in the myocardium, suggesting an anti-angiogenic role for lumican [7].…”

Section: Introductionmentioning

confidence: 99%

Lumican Reduces Tumor Growth Via Induction of Fas-Mediated Endothelial Cell Apoptosis

Williams

Fulford

Albig

2010

Cancer Microenvironment

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Matrikines are important components of tumor microenvironments that integrate communication between extracellular matricies and membrane-bound receptors thereby regulating cellular behaviors. One such matrikine that is differentially expressed in cancer microenvironments is the extracellular matrix protein lumican; however its precise role in cancer remains ambiguous. To study the effects of lumican on cancer cells, we created lumican-overexpressing cell lines from murine fibrosarcoma (MCA102) and pancreatic adenocarcinoma (Pan02) cells. Lumican overexpression in Pan02 cells increased invasiveness, decreased soft agar colony size, and increased proliferation. Conversely in MCA102 cells, lumican decreased invasiveness, increased soft agar colony size, but did not influence proliferation. In contrast to these pleiotropic in vitro results, lumican overexpression within the in vivo tumor microenvironment produced uniformly smaller tumors. Importantly, reduced tumor size was correlated with reduced vascular density. Consistent with lumican's proposed anti-angiogenic activity, lumican increased endothelial cell apoptosis. Importantly, lumican was previously shown to influence Fas expression and our results show that lumican enhanced Fas mediated endothelial cell apoptosis although we were unable to detect any difference in Fas or Fas ligand expression between lumican-overexpressing and control cells. Interestingly, lumican had no effect on MCA102 apoptosis, suggesting that the observed reduction in tumor size is specifically due to endothelial cell apoptosis rather than a direct effect on the cancerous cells themselves. Therefore, this study is the first to demonstrate a causal relationship between tumor reduction and lumican's effect on angiogenesis as opposed to an effect on the cancerous cells themselves.

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“…In human monocytic cells, TGF-␤1, but not TGF-␤2, responses are abrogated in the presence of endoglin (88). In a variety of cell types, including myoblasts and fibroblasts, endoglin opposes TGF-␤1-dependent responses such as the inhibition of cellular proliferation (88), the expression of the ECM proteoglycan lumican (22), as well as the increased expression of ECM components, including plasminogen activator inhibitor type 1 (PAI-1), collagen, or fibronectin (46,72,88,96,125). Moreover, neutralizing anti-endoglin antibodies or antisense oligonucleotides for endoglin enhance the inhibitory effect of TGF-␤ on proliferation and migration (100,152), whereas endoglin overexpression counteracts the antiproliferative effect of TGF-␤1 in ECs (100).…”

Section: Modulation By Endoglin Of Tgf-␤-dependent Cell Responsesmentioning

confidence: 99%

The physiological role of endoglin in the cardiovascular system

López‐Novoa

Bernabeu

2010

American Journal of Physiology-Heart and Circulatory Physiology

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187

200

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Endoglin (CD105) is an integral membrane glycoprotein that serves as a coreceptor for members of the transforming growth factor-β superfamily of proteins. A major role for endoglin in regulating transforming growth factor-β-dependent vascular remodeling and angiogenesis has been postulated based on the following: 1) endoglin is the gene mutated in hereditary hemorrhagic telangiectasia type 1, a disease characterized by vascular malformations; 2) endoglin knockout mice die at midgestation because of defective angiogenesis; 3) endoglin is overexpressed in neoangiogenic vessels, during inflammation, and in solid tumors; and 4) endoglin regulates the expression and activity of endothelial nitric oxide synthase, which is involved in angiogenesis and vascular tone. Besides the predominant form of the endoglin receptor (long endoglin isoform), two additional forms of endoglin have been recently reported to play a role in the vascular pathology and homeostasis: the alternatively spliced short endoglin isoform and a soluble endoglin form that is proteolytically cleaved from membrane-bound endoglin. The purpose of this review is to underline the role that the different forms of endoglin play in regulating angiogenesis, vascular remodeling, and vascular tone, as well as to analyze the molecular and cellular mechanisms supporting these effects.

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Lumican is down-regulated in cells expressing endoglin. Evidence for an inverse correlationship between Endoglin and Lumican expression

Cited by 15 publications

References 49 publications

Endoglin Modulation of TGF-ß1-Induced Collagen Synthesis is Dependent on ERK1/2 MAPK Activation

Endoglin Modulation of TGF-ß1-Induced Collagen Synthesis is Dependent on ERK1/2 MAPK Activation

Lumican Reduces Tumor Growth Via Induction of Fas-Mediated Endothelial Cell Apoptosis

The physiological role of endoglin in the cardiovascular system

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