Association of Chromatin Proteins High Mobility Group Box (HMGB) 1 and HMGB2 with Mitotic Chromosomes

Pallier, C.; Scaffidi, Paola; Chopineau-Proust, Stéphanie; Agresti, A; Nordmann, Patrice; Bianchi, Marco E.; Maréchal, Vincent

doi:10.1091/mbc.e02-09-0581

Cited by 132 publications

(132 citation statements)

References 57 publications

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“…The relative increase of the cytoplasmic per total HMGB1 protein may, at least in part, result from the dissociation of nuclear HMGB1 into the cytoplasm during mitosis of the epithelial cells (16,51). Our previous study clearly demonstrated a greater (~1.2-fold) proliferation of lung epithelial cells in the presence of fibroblasts and conditioned medium from fibroblasts, respectively, which was less pronounced by inhibiting the basic fibroblast growth factor (bFGF) (34).…”

Section: Discussionmentioning

confidence: 97%

Fibroblasts mediate induction of high mobility group box protein 1 in lung epithelial cancer cells by diffusible factors

Bartling

Fuchs²,

Silber³

et al. 2007

Int J Mol Med

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Abstract. Cancer development is associated with the high mobility group box protein 1 (HMGB1), which modulates the transcriptional activity in the nucleus, but it is also present in the cytoplasm and outside the cell in certain conditions. As the progression of lung cancer is supported by mitogenic stimuli of stromal fibroblasts, we studied the impact of lung fibroblasts (WI-38) on the expression and localization of HMGB1 in lung epithelial cancer cells (H358). HMGB1 was mainly localized in the nucleus of non-mitotic H358 cells but highly distributed in the cytoplasm of mitotic cells. Conditioned medium (CM) from WI-38 fibroblasts enhanced the expression of HMGB1 at the mRNA and protein level compared to the control CM from H358 cells. In particular, the amount of cytoplasmic HMGB1 was elevated in response to fibroblast CM, which was reduced by inhibiting the basic fibroblast growth factor with blocking antibodies. Although cytoplasmic HMGB1 can be released from the cell, we did not determine a significant amount of extracellular HMGB1 in these conditions. This might partially be based on the sensitivity of HMGB1 to extracellular proteases as CM caused fast proteolysis of the cytoplasmic HMGB1 preparations. Our data suggest that diffusible factors of fibroblasts support the biological function of cancer cells via HMGB1 activation.

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Section: Discussionmentioning

confidence: 97%

Fibroblasts mediate induction of high mobility group box protein 1 in lung epithelial cancer cells by diffusible factors

Bartling

Fuchs²,

Silber³

et al. 2007

Int J Mol Med

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“…Thus, it is hypothesized that the close proximity of both NLSs in a resting state is disturbed by concomitant phosphorylation at the regions close to the NLSs when stimulated. In the study of HMGB2 (previously HMG2) protein, which has high sequence similarities with HMGB1, the acidic carboxyl terminus influences its retention in the nucleus (38,39). Thus, we are now studying the role of the HMGB1 acidic tail in the nuclear transport of the protein because HMGB1 and HMGB2 are not structurally and functionally the same (40,41).…”

Section: Discussionmentioning

confidence: 99%

Nucleocytoplasmic Shuttling of HMGB1 Is Regulated by Phosphorylation That Redirects It toward Secretion

Youn

Shin

2006

The Journal of Immunology

315

330

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The high mobility group box 1 (HMGB1) protein can be secreted by activated monocytes and macrophages and functions as a late mediator of sepsis. HMGB1 contains two nuclear localization signals (NLSs) for controlled nuclear transport, and acetylation of both NLSs of HMGB1 is involved in nuclear transport toward secretion. However, phosphorylation of HMGB1 and its relation to nuclear transport have not been shown. We show here that HMGB1 is phosphorylated and dynamically shuttled between cytoplasmic and nuclear compartments according to its phosphorylation state. Phosphorylation of HMGB1 was detected by metabolic labeling and Western blot analysis after treatments with TNF-α and okadaic acid, a phosphatase inhibitor. Hyperphosphorylated HMGB1 in RAW 264.7 and human monocytes was relocated to the cytoplasm. In a nuclear import assay, phosphorylated HMGB1 in the cytoplasm did not enter the nucleus. We mutated serine residues of either or both NLSs of HMGB1 to glutamic acid to simulate a phosphorylated state and examined the binding of HMGB1 to karyopherin-α1, which was identified as the nuclear import protein for HMGB1 in this study. Substitution to glutamic acid in either NLSs decreased the binding with karyopherin-α1 by ∼ 50%; however, substitution of both NLSs showed no binding, and HMGB1 was relocated to the cytoplasm and subsequently secreted. These data support the hypothesis that HMGB1 could be phosphorylated and that the direction of transport is regulated by phosphorylation of both NLS regions.

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“…Tumorzellen k ö nnen diese nat ü rliche Replikationsbeschr ä nkung ü berwinden, indem sie mit speziellen Telomerasen die Telomere wieder verl ä ngern und damit nie die kritische L ä nge unterschreiten [95,96] . HMGB1 als DNA-bindendes Chaperon interagiert auch mit Chromosomen in der Mitose, wie in vivo wurde, [97] und nachgewiesen mit einer Haarnadelstruktur auf einem Telomer wie explizit bei dem Parvovirus " minute virus of mice " festgestellt wurde [98] .…”

Section: Unbegrenztes Replikationspotentialunclassified

Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen/Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

Wittwer¹,

Holdenrieder²

2013

Laboratoriumsmedizin

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ZusammenfassungImmunogene Zelltodmarker sind eine inhomogene Gruppe von Molekülen, die während Zelltodprozessen wie Apoptose, Nekrose oder weiteren Formen freigesetzt werden. Je nach Zusammensetzung des extrazellulären Milieus können diese „Danger associated molecular patterns“ (DAMPs) wie das „High mobility group box 1“ (HMGB1) Protein das Immunsystem stimulierend oder inhibierend beeinflussen. Bei Tumorerkrankungen scheint eine kontinuierliche Freisetzung von HMGB1, u.a. über eine Vermittlung durch den zellulären Bindungspartner „Receptor of advanced glycation end products“ (RAGE), zu einer Förderung des Tumorwachstums zu führen, während die pulsatile Freisetzung während zytotoxischer Therapie zu einer verbesserten antitumorösen Immunantwort beitragen könnte. Lösliches RAGE (sRAGE) kann hingegen die Effekte von extrazellulärem HMGB1 abpuffern. In diesem Review werden die strukturellen und funktionalen Charakteristika dieser immunogenen Zelltodmarker sowie ihre Rolle in der Pathophysiologie von nicht-malignen und malignen Erkrankungen vorgestellt; sodann wird ihre Relevanz als Serum-Biomarker für die Diagnose, die Prognoseabschätzung, die Prädiktion und das Monitoring des Ansprechens einer zytotoxischen Therapie bei Tumorpatienten beleuchtet. Bei Patienten mit verschiedenen Tumorerkrankungen wurden im Vergleich zu gesunden Personen erhöhte Serumkonzentrationen von HMGB1 und niedrigere sRAGE-Werte gefunden. Zudem waren hohe HMGB1- und niedrige sRAGE-Serumwerte vor und während einer zytotoxischen Therapie mit einem unzureichenden Ansprechen auf die Behandlung und einem kürzeren Überleben assoziiert. Diese Ergebnisse weisen die immunogenen Zelltodmarker HMGB1 und sRAGE als neue, vielversprechende Biomarker zur Abschätzung der Prognose, Stratifikation der Patienten und zum Therapiemonitoring bei Tumorpatienten aus.

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Association of Chromatin Proteins High Mobility Group Box (HMGB) 1 and HMGB2 with Mitotic Chromosomes

Cited by 132 publications

References 57 publications

Fibroblasts mediate induction of high mobility group box protein 1 in lung epithelial cancer cells by diffusible factors

Fibroblasts mediate induction of high mobility group box protein 1 in lung epithelial cancer cells by diffusible factors

Nucleocytoplasmic Shuttling of HMGB1 Is Regulated by Phosphorylation That Redirects It toward Secretion

Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen/Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

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