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The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells.

Degryse B, Bonaldi T, Scaffidi P, Müller S, Resnati M, Sanvito F, Arrigoni G, Bianchi ME - J. Cell Biol. (2001)

Bottom Line: HMG1 (and its individual DNA-binding domains) stimulated migration of rat smooth muscle cells in chemotaxis, chemokinesis, and wound healing assays.HMG1 induced rapid and transient changes of cell shape, and actin cytoskeleton reorganization leading to an elongated polarized morphology typical of motile cells.These effects were inhibited by antibodies directed against the receptor of advanced glycation endproducts, indicating that the receptor of advanced glycation endproducts is the receptor mediating the HMG1-dependent migratory responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Microbiology, University of Milan, 20133 Milan, Italy. degryse@scripps.edu

ABSTRACT
HMG1 (high mobility group 1) is a ubiquitous and abundant chromatin component. However, HMG1 can be secreted by activated macrophages and monocytes, and can act as a mediator of inflammation and endotoxic lethality. Here we document a role of extracellular HMG1 in cell migration. HMG1 (and its individual DNA-binding domains) stimulated migration of rat smooth muscle cells in chemotaxis, chemokinesis, and wound healing assays. HMG1 induced rapid and transient changes of cell shape, and actin cytoskeleton reorganization leading to an elongated polarized morphology typical of motile cells. These effects were inhibited by antibodies directed against the receptor of advanced glycation endproducts, indicating that the receptor of advanced glycation endproducts is the receptor mediating the HMG1-dependent migratory responses. Pertussis toxin and the mitogen-activated protein kinase kinase inhibitor PD98059 also blocked HMG1-induced rat smooth muscle cell migration, suggesting that a G(i/o) protein and mitogen-activated protein kinases are required for the HMG1 signaling pathway. We also show that HMG1 can be released by damage or necrosis of a variety of cell types, including endothelial cells. Thus, HMG1 has all the hallmarks of a molecule that can promote atherosclerosis and restenosis after vascular damage.

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The MAP kinase pathway is involved in HMG1 signaling. RSMC, pretreated or not for 1 h with 50 μM PD98059, were stimulated for 30 min with 100 ng/ml calf thymus HMG1. Cells were then stained with antibodies against phosphorylated ERK1/2 and DAPI. A separate sample of cells were stained with TRITC-phalloidin to visualize the reorganization of the cytoskeleton.
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Figure 7: The MAP kinase pathway is involved in HMG1 signaling. RSMC, pretreated or not for 1 h with 50 μM PD98059, were stimulated for 30 min with 100 ng/ml calf thymus HMG1. Cells were then stained with antibodies against phosphorylated ERK1/2 and DAPI. A separate sample of cells were stained with TRITC-phalloidin to visualize the reorganization of the cytoskeleton.

Mentions: We next investigated whether HMG1 signaling involves the MAP kinase pathway, which is known to respond to RAGE and to activate directly the intracellular motility machinery. Within 30 min, HMG1 activated ERK1/2 proteins in RSMC and induced their nuclear translocation (Fig. 7). In contrast, phosphorylated ERK proteins were hardly detectable and located in the cytoplasm, in unstimulated RSMC. PD98059, the selective inhibitor of MEK, the upstream regulator of ERK, inhibited HMG1-induced ERK phosphorylation and nuclear translocation. HMG1-induced RSMC migration and cytoskeleton reorganization was also inhibited by PD98059 (Fig. 7, and results not shown). Thus, the MAP kinase pathway appears to play an essential role in HMG1-induced cell migration.


The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells.

Degryse B, Bonaldi T, Scaffidi P, Müller S, Resnati M, Sanvito F, Arrigoni G, Bianchi ME - J. Cell Biol. (2001)

The MAP kinase pathway is involved in HMG1 signaling. RSMC, pretreated or not for 1 h with 50 μM PD98059, were stimulated for 30 min with 100 ng/ml calf thymus HMG1. Cells were then stained with antibodies against phosphorylated ERK1/2 and DAPI. A separate sample of cells were stained with TRITC-phalloidin to visualize the reorganization of the cytoskeleton.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199202&req=5

Figure 7: The MAP kinase pathway is involved in HMG1 signaling. RSMC, pretreated or not for 1 h with 50 μM PD98059, were stimulated for 30 min with 100 ng/ml calf thymus HMG1. Cells were then stained with antibodies against phosphorylated ERK1/2 and DAPI. A separate sample of cells were stained with TRITC-phalloidin to visualize the reorganization of the cytoskeleton.
Mentions: We next investigated whether HMG1 signaling involves the MAP kinase pathway, which is known to respond to RAGE and to activate directly the intracellular motility machinery. Within 30 min, HMG1 activated ERK1/2 proteins in RSMC and induced their nuclear translocation (Fig. 7). In contrast, phosphorylated ERK proteins were hardly detectable and located in the cytoplasm, in unstimulated RSMC. PD98059, the selective inhibitor of MEK, the upstream regulator of ERK, inhibited HMG1-induced ERK phosphorylation and nuclear translocation. HMG1-induced RSMC migration and cytoskeleton reorganization was also inhibited by PD98059 (Fig. 7, and results not shown). Thus, the MAP kinase pathway appears to play an essential role in HMG1-induced cell migration.

Bottom Line: HMG1 (and its individual DNA-binding domains) stimulated migration of rat smooth muscle cells in chemotaxis, chemokinesis, and wound healing assays.HMG1 induced rapid and transient changes of cell shape, and actin cytoskeleton reorganization leading to an elongated polarized morphology typical of motile cells.These effects were inhibited by antibodies directed against the receptor of advanced glycation endproducts, indicating that the receptor of advanced glycation endproducts is the receptor mediating the HMG1-dependent migratory responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Microbiology, University of Milan, 20133 Milan, Italy. degryse@scripps.edu

ABSTRACT
HMG1 (high mobility group 1) is a ubiquitous and abundant chromatin component. However, HMG1 can be secreted by activated macrophages and monocytes, and can act as a mediator of inflammation and endotoxic lethality. Here we document a role of extracellular HMG1 in cell migration. HMG1 (and its individual DNA-binding domains) stimulated migration of rat smooth muscle cells in chemotaxis, chemokinesis, and wound healing assays. HMG1 induced rapid and transient changes of cell shape, and actin cytoskeleton reorganization leading to an elongated polarized morphology typical of motile cells. These effects were inhibited by antibodies directed against the receptor of advanced glycation endproducts, indicating that the receptor of advanced glycation endproducts is the receptor mediating the HMG1-dependent migratory responses. Pertussis toxin and the mitogen-activated protein kinase kinase inhibitor PD98059 also blocked HMG1-induced rat smooth muscle cell migration, suggesting that a G(i/o) protein and mitogen-activated protein kinases are required for the HMG1 signaling pathway. We also show that HMG1 can be released by damage or necrosis of a variety of cell types, including endothelial cells. Thus, HMG1 has all the hallmarks of a molecule that can promote atherosclerosis and restenosis after vascular damage.

Show MeSH
Related in: MedlinePlus