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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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Related in: MedlinePlus

Effects of HMG1 and its HMG boxes on RSMC migration into a wound. Monolayers were wounded and allowed to recover for 48 h in the presence of the indicated molecules. Then, RSMC that had migrated into the wound were counted as described in Materials and Methods. The value of 100% corresponds to the number of cells migrating in the absence of any stimulator (random cell migration). The data represent the mean ± SD (n = 5). Statistical significance was 0.05 < P < 0.01 for treatment with bFGF and full-length E. coli–made HMG1, 0.01 < P < 0.001 for treatment with Box A and Box B, and 0.001 < P < 0.0001 for treatment with calf thymus HMG1.
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Figure 4: Effects of HMG1 and its HMG boxes on RSMC migration into a wound. Monolayers were wounded and allowed to recover for 48 h in the presence of the indicated molecules. Then, RSMC that had migrated into the wound were counted as described in Materials and Methods. The value of 100% corresponds to the number of cells migrating in the absence of any stimulator (random cell migration). The data represent the mean ± SD (n = 5). Statistical significance was 0.05 < P < 0.01 for treatment with bFGF and full-length E. coli–made HMG1, 0.01 < P < 0.001 for treatment with Box A and Box B, and 0.001 < P < 0.0001 for treatment with calf thymus HMG1.

Mentions: To independently confirm the results obtained with the chemotaxis and chemokinesis assays, we used an in vitro wound-healing assay. Confluent monolayers of serum-starved RSMC were wounded and then stimulated for 48 h with HMG1, either from calf thymus or E. coli. Both HMG1 preparations increased the number of migrating cells by ∼1.5–2-fold (Fig. 4). We also tested Box A and Box B (at 10 ng/ml each): both stimulated cell migration ∼1.8-fold. HMG1 and its derivatives were more effective than bFGF (50 ng/ml), which increased cell migration ∼1.5-fold.


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)

Effects of HMG1 and its HMG boxes on RSMC migration into a wound. Monolayers were wounded and allowed to recover for 48 h in the presence of the indicated molecules. Then, RSMC that had migrated into the wound were counted as described in Materials and Methods. The value of 100% corresponds to the number of cells migrating in the absence of any stimulator (random cell migration). The data represent the mean ± SD (n = 5). Statistical significance was 0.05 < P < 0.01 for treatment with bFGF and full-length E. coli–made HMG1, 0.01 < P < 0.001 for treatment with Box A and Box B, and 0.001 < P < 0.0001 for treatment with calf thymus HMG1.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Effects of HMG1 and its HMG boxes on RSMC migration into a wound. Monolayers were wounded and allowed to recover for 48 h in the presence of the indicated molecules. Then, RSMC that had migrated into the wound were counted as described in Materials and Methods. The value of 100% corresponds to the number of cells migrating in the absence of any stimulator (random cell migration). The data represent the mean ± SD (n = 5). Statistical significance was 0.05 < P < 0.01 for treatment with bFGF and full-length E. coli–made HMG1, 0.01 < P < 0.001 for treatment with Box A and Box B, and 0.001 < P < 0.0001 for treatment with calf thymus HMG1.
Mentions: To independently confirm the results obtained with the chemotaxis and chemokinesis assays, we used an in vitro wound-healing assay. Confluent monolayers of serum-starved RSMC were wounded and then stimulated for 48 h with HMG1, either from calf thymus or E. coli. Both HMG1 preparations increased the number of migrating cells by ∼1.5–2-fold (Fig. 4). We also tested Box A and Box B (at 10 ng/ml each): both stimulated cell migration ∼1.8-fold. HMG1 and its derivatives were more effective than bFGF (50 ng/ml), which increased cell migration ∼1.5-fold.

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