Immunoreactivity to Cell Surface Syndecans in Cytoplasm and Nucleus: Tubulin-Dependent Rearrangements

Brockstedt, Ulrika; Dobra, Katalin; Nurminen, M.; Hjerpe, Anders

doi:10.1006/excr.2002.5477

Cited by 64 publications

(82 citation statements)

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“…One possibility is that heparanase and syndecan-1 are transported together as a complex through an interaction between syndecan-1 heparan sulfate chains and heparan sulfate binding domains known to be present within heparanase. Studies utilizing immunofluorescence microscopy indicate that in some tumor types, syndecan-1 transport to the nucleus is tubulin-dependent and that nuclear translocation requires the RMKKK sequence present within the syndecan-1 core protein (20,38). If bound to syndecan-1, heparanase could be transported via this same route assuming that the tubulin-mediated transport route is active in myeloma cells.…”

Section: Discussionmentioning

confidence: 99%

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Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Purushothaman

Hurst

Pisano

et al. 2011

Journal of Biological Chemistry

102

116

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Heparanase acts as a master regulator of the aggressive tumor phenotype in part by enhancing expression of proteins known to drive tumor progression (e.g. VEGF, MMP-9, hepatocyte growth factor (HGF), and RANKL). However, the mechanism whereby this enzyme regulates gene expression remains unknown. We previously reported that elevation of heparanase levels in myeloma cells causes a dramatic reduction in the amount of syndecan-1 in the nucleus. Because syndecan-1 has heparan sulfate chains and because exogenous heparan sulfate has been shown to inhibit the activity of histone acetyltransferase (HAT) enzymes in vitro, we hypothesized that the reduction in nuclear syndecan-1 in cells expressing high levels of heparanase would result in increased HAT activity leading to stimulation of protein transcription. We found that myeloma cells or tumors expressing high levels of heparanase and low levels of nuclear syndecan-1 had significantly higher levels of HAT activity when compared with cells or tumors expressing low levels of heparanase. High levels of HAT activity in heparanase-high cells were blocked by SST0001, an inhibitor of heparanase. Restoration of high syndecan-1 levels in heparanase-high cells diminished nuclear HAT activity, establishing syndecan-1 as a potent inhibitor of HAT. Exposure of heparanase-high cells to anacardic acid, an inhibitor of HAT activity, significantly suppressed their expression of VEGF and MMP-9, two genes known to be up-regulated following elevation of heparanase. These results reveal a novel mechanistic pathway driven by heparanase expression, which leads to decreased nuclear syndecan-1, increased HAT activity, and up-regulation of transcription of multiple genes that drive an aggressive tumor phenotype.Heparanase, an endoglycosidase that cleaves heparan sulfate, is up-regulated in many cancers where it promotes tumor growth, angiogenesis, and metastasis (1, 2). High levels of heparanase in cancer patients are associated with shorter postoperative survival time compared with patients with low levels of heparanase (1). Although some of the tumor promoting effects of heparanase can be attributed to its ability to remodel the extracellular matrix barrier by cleaving heparan sulfate, heparanase is also known to regulate cell signaling and gene transcription (1, 3-5). Elevation of heparanase levels in myeloma cells, either by transfection of cells or by addition of recombinant active heparanase enzyme to cells, up-regulates expression of MMP-9, VEGF, HGF, 2 and RANKL, which together drive an aggressive tumor phenotype (6 -9). Although the mechanism whereby heparanase drives gene expression remains unknown, the enzyme is present and active in the nucleus where it could act locally to regulate gene expression (10).Acetylation of the N-terminal tails of histones by histone acetyltransferase enzymes has been known for many years to be a process correlating with transcriptional activation (11)(12)(13)(14). This process is balanced by the activity of histone deacetylases (HDACs), which selectivel...

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Section: Discussionmentioning

confidence: 99%

“…There are numerous reports that heparan sulfate proteoglycans localize within the nucleus (17)(18)(19)(20). We recently discovered that the syndecan-1 heparan sulfate-bearing proteoglycan is present in the nucleus of myeloma tumor cells and that the amount of nuclear syndecan-1 is dramatically reduced upon elevation of heparanase expression (21).…”

mentioning

confidence: 99%

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Purushothaman

Hurst

Pisano

et al. 2011

Journal of Biological Chemistry

102

116

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“…Фактор роста гепато-цитов HGF, связанный с цепями ГС синдекана 1, се-кретированного в культуральную среду опухолевыми клетками миеломы, транспортируется в ядра нормаль-ных клеток стромы костного мозга вместе с синдека-ном 1, а удаление связанного с ГС фактора роста гепато-цитов из комплекса отменяет транслокацию синдекана 1 в ядро [115]. Молекулярный механизм такой транс-локации в клетках мезотелиомы связан с прямым вза-имодействием углеводных цепей ГС с микротрубочками [119], а макромолекулярный комплекс синдекана 1 и тубулина может принимать участие в переносе фак-торов роста в ядро клетки.…”

Section: функциональная роль внутриядерных протеогликановunclassified

“…Версикан, по-видимому, играет роль в органи-зации митотического веретена деления во время деле-ния эндотелиальных клеток крысы [108], а присутствие синдекана 1 в митотическом веретене деления может стабилизировать митотический механизм в клетках мезотелиомы [119]. Индуцированная винбластином (химиопрепарат, который связывается с тубулином и тормозит образование веретена деления) остановка деления клеток в фазе G 2 ингибирует транслокацию синдекана 1 в ядро [118].…”

Section: функциональная роль внутриядерных протеогликановunclassified

Proteoglycans in normal physiology and carcinogenesis

Суховских¹,

Григорьева²

2018

Usp. mol. onkol

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“…A more recent study indicated that heparanase also regulates levels of syndecan-1 in the nucleus (Chen and Sanderson, 2009). A number of potential roles of heparan sulfate in the nucleus have been suggested for regulation of cell proliferation, inhibition of DNA topoisomerase I, inhibition of histone acetyltransferase (HAT), control of cell division, and nuclear localization of basic FGF (Fedarko et al, 1989;Kovalszky et al, 1998;Brockstedt et al, 2002;Dobra et al, 2003;Hsia et al, 2003). The shed syndecans via their heparin sulfate chains are active and working as a signaling mediators for cell-cell interaction, cell survival, cell migration (Couchman et al, 2001;Perrimon and Bernfi eld, 2001;Sanderson, 2001;Couchman, 2003;Beauvais and Rapraeger, 2004;Tkachenko et al, 2005).…”

Section: Soluble Syndecans and Tumormentioning

confidence: 99%

Syndecan as a Messenger to Link Diabetes and Cancer

Kim

Raman²

2011

Biomolecules and Therapeutics

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Cell surface syndecans are membrane-anchored proteoglycans. These glycoproteins have covalently linked glycosaminoglycan side chains. They interact via their extracellular part with various growth factors, extracellular matrix components, other cell surface molecules, and proteins involved in the regulation of blood coagulation. Thus the syndecans involve in synchronized expression patterns during embryogenesis and malignant transformation. These cell-cell interactions via their extracellular matrix ligands control cell proliferation, dynamic cytoskeletal remodeling, apoptosis and gene expression.Over the last few years, it has been widely accepted that heparan sulfate proteoglycans play a role in growth control, cell spreading, cellular recognition, cellular adhesion, and signaling, possibly as co -receptors with integrins, IGF-1R and cell -cell adhesion molecules, including fi bronectin, vitronectin, laminins, and the fi brillar collagens (Bernfi eld et al., 1999;Woods, 2001;Alexopoulou et al., 2007;Beauvais and Rapraeger, 2010). In addition, all syndecans have dibasic peptide sequence adjacent to the plasma membrane. Thus, the extracellular domains of syndecans could be cleaved by extracellular proteases. Syndecan's ectodomains have been shown to regulate a multitude of biological functions in celldependent and cell-independent approaches (Li et al., 2002;Endo et al., 2003;Elenius et al., 2004). Soluble syndecans also convert the membrane-bound receptors into soluble effectors/or antagonists. The soluble ectodomains of syndecans can compete with intact syndecans for extracellular ligands (Steinfeld et al., 1996). In this review, we will discuss the general Syndecans are membrane-anchored proteoglycans and implicated in the pathogenesis of cancer progression and metastasis. Syndecans also play important roles in interacting with growth factors, extracellular matrix and other cell surface molecules such as IGF-1 receptor. In the present review, we discuss about the syndecan structure, their role in signaling with other receptors, in addition to its general biology. The emerging roles of syndecans in the pathophysiology of human diseases, especially insulin resistance, diabetes and cancer is discussed. Abstractfeatures and their conventional roles in signaling with co-receptors. Finally, we will explore the emerging roles of syndecans in the pathophysiology of human diseases, especially type 2 diabetes. SYNDECAN STRUCTUREAll the syndecans are a type 1 transmembrane proteins that are expressed in almost every cell of the body. Four members of syndecan family have been identifi ed in mammalians such as syndecan-1, 2, 3, and 4. Syndecan-1 analogs are also identifi ed in other mammals such as mouse, rat, dog, chimpanzee, guinea pig, Chinese hamster, cat and chicken. The extracellular domains of human and mouse syndecan-1 display approximately 70% sequence homology whereas the transmembrane domain and cytoplasmic domain show 96 % and 100% sequence homology, respectively. Synthesis of four syndecan core proteins are ...

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Immunoreactivity to Cell Surface Syndecans in Cytoplasm and Nucleus: Tubulin-Dependent Rearrangements

Cited by 64 publications

References 31 publications

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Proteoglycans in normal physiology and carcinogenesis

Syndecan as a Messenger to Link Diabetes and Cancer

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