Trans-repressor activity of nuclear glycosaminoglycans on Fos and Jun/AP-1 oncoprotein-mediated transcription.

Busch, Steve; Martin, Grégoire; Barnhart, Roger L.; Mano, Miguel; Cardin, Alan D.; Jackson, R L

doi:10.1083/jcb.116.1.31

Cited by 117 publications

(78 citation statements)

References 76 publications

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“…Hyaluronic acid, chondroitin sulfate, and dermatan sulfate are also associated with the nucleus in amounts that cannot be explained by adventitious association during cell fractionation (Margolis et al, 1975;Furukawa and Terayama, 1977;Hiscock et al, 1994). The basic DNA-binding sequences of several transcription factors resemble high-affinity heparinbinding consensus sequences, and many transcription factors are retained on heparin affinity columns (Jackson et al, 1991); endogenous nuclear glycosaminoglycans have been implicated in regulating the action of Fos and Jun/AP-1 (Busch et al, 1992), although it is not clear whether they act by inhibiting DNA binding.…”

Section: Glycolytic Enzymesmentioning

confidence: 99%

Proteins in unexpected locations.

Smalheiser

1996

MBoC

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Members of all classes of proteins--cytoskeletal components, secreted growth factors, glycolytic enzymes, kinases, transcription factors, chaperones, transmembrane proteins, and extracellular matrix proteins--have been identified in cellular compartments other than their conventional sites of action. Some of these proteins are expressed as distinct compartment-specific isoforms, have novel mechanisms for intercompartmental translocation, have distinct endogenous biological actions within each compartment, and are regulated in a compartment-specific manner as a function of physiologic state. The possibility that many, if not most, proteins have distinct roles in more than one cellular compartment has implications for the evolution of cell organization and may be important for understanding pathological conditions such as Alzheimer's disease and cancer.

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Section: Glycolytic Enzymesmentioning

confidence: 99%

Proteins in unexpected locations.

Smalheiser

1996

MBoC

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“…In addition, several other observations for the apoptotic activities of heparin have been reported (5,6). For example, heparin inhibits activator protein-1, which is the nuclear target of many oncogenic signal transduction pathways (7), and it may bind with DNA through charge to charge interaction; in turn, transcription factors can be upregulated in both the cytosol and the nucleus (8).…”

Section: Introductionmentioning

confidence: 99%

Antiangiogenic and Apoptotic Properties of a Novel Amphiphilic Folate-Heparin-Lithocholate Derivative Having Cellular Internality for Cancer Therapy

Lee

Kim

et al. 2007

Pharm Res

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Purpose. Anitangiogenic and apoptotic properties of a novel chemically modified heparin derivative with low anticoagulant activity were evaluated on the experimental in vitro and in vivo model. Materials and Methods. Heparin-lithocholate conjugate (HL) was initially synthesized by covalently bonding lithocholate to heparin. Folate-HL conjugate (FHL) was further synthesized by conjugating folate to HL. Antiangiogenic and apoptotic abilities of HL and FHL were characterized in vitro and in vivo experimentations. Results. Compared to unmodified heparin, both HL and FHL represented a low anticoagulant activity (38 and 28%, respectively). HL and FHL maintained antiangiogenic activity even further modification from the results of Matrigel plugs assay. FHL specifically induced apoptosis on KB cells having highly expressed folate receptor after cellular internalization. Both administered HL and FHL had similar antiangiogenic activity and inhibitory effect on tumor growth in vivo although FHL induced higher apoptosis on tumor tissues. Conclusions. In vivo tumor growth inhibition was possibly due to the decrease of vessel density and apoptotic cell death, although antiangiogenic effect of FHL seemed more actively affected on growth inhibition than apoptotic potential in vivo system. Thus, Low anticoagulant FHL having antiangiogenic and apoptotic properties would provide benefits for the development of a new class of anticancer agent.

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“…Reports of fluorescent heparin uptake into cells, where it modulated transcription factor function (17), and the requirements of HSPGs for basic growth factor delivery to the nucleus (18) indicate that receptor-mediated uptake of heparin or HS may also be critical for some heparin effects. Similarly, shed HSPG syndecan-1 can be taken up by cells and transported to the nucleus, where it alters histone acetylation (19).…”

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confidence: 99%

Transmembrane Protein 184A Is a Receptor Required for Vascular Smooth Muscle Cell Responses to Heparin

Pugh

Slee

Farwell³

et al. 2016

Journal of Biological Chemistry

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Vascular cell responses to exogenous heparin have been documented to include decreased vascular smooth muscle cell proliferation following decreased ERK pathway signaling. However, the molecular mechanism(s) by which heparin interacts with cells to induce those responses has remained unclear. Previously characterized monoclonal antibodies that block heparin binding to vascular cells have been found to mimic heparin effects. In this study, those antibodies were employed to isolate a heparin binding protein. MALDI mass spectrometry data provide evidence that the protein isolated is transmembrane protein 184A (TMEM184A). Commercial antibodies against three separate regions of the TMEM184A human protein were used to identify the TMEM184A protein in vascular smooth muscle cells and endothelial cells. A GFP-TMEM184A construct was employed to determine colocalization with heparin after endocytosis. Knockdown of TMEM184A eliminated the physiological responses to heparin, including effects on ERK pathway activity and BrdU incorporation. Isolated GFP-TMEM184A binds heparin, and overexpression results in additional heparin uptake. Together, these data support the identification of TMEM184A as a heparin receptor in vascular cells.For more than 30 years, heparin has been known to specifically bind to cells in the vasculature and alter their physiology in addition to its well recognized function as an anticoagulant. Heparin binds to many proteins, including numerous growth factors, cytokines, coagulation factors, cell adhesion molecules, growth factor receptors, matrix glycoproteins, and others (for a review, see Ref. 1). In fact, heparin and the closely related glycosaminoglycan heparan sulfate (HS), 4 interact with more than 400 proteins (2). Heparin decreases endothelial cell (EC) inflammatory gene expression and slows vascular smooth muscle cell (VSMC) proliferation (reviewed in Ref. 3). Specifically, ECs bind and endocytose heparin (4, 5), which is followed by decreased inflammatory signaling through NF-B (6) and stress kinase activity (7,8). Heparin binding in VSMCs (9) results in decreases in growth factor-induced ERK signaling (10, 11), inhibition of downstream transcription factor activity (12-14), changes in cell cycle inhibitory factors (15), and decreased proliferation (10, 16).Reports of fluorescent heparin uptake into cells, where it modulated transcription factor function (17), and the requirements of HSPGs for basic growth factor delivery to the nucleus (18) indicate that receptor-mediated uptake of heparin or HS may also be critical for some heparin effects. Similarly, shed HSPG syndecan-1 can be taken up by cells and transported to the nucleus, where it alters histone acetylation (19). HS chains are required for uptake, and this uptake can be inhibited by exogenously added heparin. It is likely that the uptake of highly charged heparin and HS chains involves a receptor to manage transport across the membrane. Although many heparin-interacting proteins have been linked to specific functions, a receptor respon...

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Trans-repressor activity of nuclear glycosaminoglycans on Fos and Jun/AP-1 oncoprotein-mediated transcription.

Abstract: Abstract. Heparin blocks the phorbol ester-induced progression of nontransformed cells through the Go/G, phase

Cited by 117 publications

References 76 publications

Proteins in unexpected locations.

Proteins in unexpected locations.

Antiangiogenic and Apoptotic Properties of a Novel Amphiphilic Folate-Heparin-Lithocholate Derivative Having Cellular Internality for Cancer Therapy

Transmembrane Protein 184A Is a Receptor Required for Vascular Smooth Muscle Cell Responses to Heparin

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