Disease relevance of HMGB1

• Apoptotic cells do not release HMGB1 even after undergoing secondary necrosis and partial autolysis, and thus fail to promote inflammation even if not cleared promptly by phagocytic cells [1].
• Comparative analysis of the respective spot patterns on two-dimensional electrophoresis showed that HMGB1, an intranuclear protein that interacts with several transcription factors and plays a role in tumor metastasis after its secretion, was overexpressed in GISTs with KIT mutation [2].
• Here we demonstrate that in contrast to the proinflammatory role of HMGB1, preconditioning with HMGB1 results in protection following hepatic ischemia/reperfusion (I/R) [3].
• Treatment with cultured medium of HMGB1/amphoterin-secreting WiDr human colon cancer cells showed growth inhibition of both U937 and PMA-U937 cells and apoptosis in PMA-U937 cells [4].
• Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule [5].

Psychiatry related information on HMGB1

• HMGB-1 binds preferentially to aggregated alpha-synuclein and is present in alpha-synuclein filament-containing Lewy bodies isolated from brain tissue affected with dementia with Lewy bodies or Parkinson's disease [6].

High impact information on HMGB1

• The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis [7].
• Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours [8].
• The structure of the complex reveals the origin of sequence-specific binding within the HMG-1/HMG-2 family and provides a framework for understanding the effects of point mutations that cause 46X,Y sex reversal at the atomic level [9].
• The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene [10].
• Microinjection of the nonhistone chromosomal protein HMG1 into bovine fibroblasts and HeLa cells [11].

Chemical compound and disease context of HMGB1

• The effects of HMGB1 overexpression in a BG-1 ovarian cancer cell line, induced by steroid hormones, on the sensitivity of cells treated with [Pt(1R,2R-diaminocyclohexane)Cl(2)] and cis-[Pt(NH(3))(cyclohexylamine)Cl(2)] were also examined [12].
• The 2--3-fold increase in HMGB1 expression observed in proliferating cells or breast cancer cells stimulated by estrogen may probably result from the action of the enhancer elements in intron 1 [13].
• The present study was therefore undertaken to investigate how HMGB-1 is expressed in muscle tissue of patients with myositis and, if so, whether such expression is modulated by prednisolone therapy [14].
• In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease [15].
• These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis [15].

Biological context of HMGB1

• Previous studies based on immunofluorescence analysis indicated that HMGB1 dissociates from chromosomes during mitosis [16].
• Nucleocytoplasmic Shuttling of HMGB1 Is Regulated by Phosphorylation That Redirects It toward Secretion [17].
• Both HMG box domains of HMGB1, A and B, interact with p73alpha [18].
• High mobility group B1 (HMGB1) is a recently identified damage-associated molecular pattern that is released during necrotic cell death and also secreted from activated macrophages, NK cells, and mature myeloid dendritic cells [19].
• In addition, HMGB1 prevented the CpG induced up-regulation of costimulatory molecules on the surface of PDC and potently suppressed their ability to drive generation of IFN-gamma-secreting T cells [19].

Anatomical context of HMGB1

• HMGB1 is secreted by activated monocytes and macrophages, and is passively released by necrotic or damaged cells [1].
• HMGB1 can also be secreted by activated monocytes and macrophages, and functions as a late mediator of inflammation [20].
• Monocytes and macrophages acetylate HMGB1 extensively upon activation with lipopolysaccharide; moreover, forced hyperacetylation of HMGB1 in resting macrophages causes its relocalization to the cytosol [20].
• Cytosolic HMGB1 is then concentrated by default into secretory lysosomes, and secreted when monocytic cells receive an appropriate second signal [20].
• Here we examine the effects of HMGB1 on human endothelial cell function [21].

Associations of HMGB1 with chemical compounds

• Substitution to glutamic acid in either NLSs decreased the binding with karyopherin-alpha1 by approximately 50%; however, substitution of both NLSs showed no binding, and HMGB1 was relocated to the cytoplasm and subsequently secreted [17].
• Inside the cell, HMGB1 binds to DNA and modulates a variety of processes, including transcription [22].
• The role of IFN-alpha and nitric oxide in the release of HMGB1 by RAW 264.7 cells stimulated with polyinosinic-polycytidylic acid or lipopolysaccharide [22].
• Dexamethasone, a known inhibitor of NF-kappaB signaling in U1 cells, inhibited HMGB1-induced stimulation of the viral production [23].
• Strikingly, HMGB1 rapidly increased integrin affinity and induced integrin polarization [24].

Physical interactions of HMGB1

• The role of the C-terminal extension (CTE) of the estrogen receptor alpha and beta DNA binding domain in DNA binding and interaction with HMGB [25].
• High mobility group protein 1 interacts specifically with the core domain of human TATA box-binding protein and interferes with transcription factor IIB within the pre-initiation complex [26].
• Only the full-length p53 can form stable ternary complexes with hcDNA and HMGB1 [27].
• Here we show that the RAG1 homeodomain directly interacts with both HMG boxes of HMG1 and HMG2 (HMG1,2) [28].
• In addition, HMG1 bound to Abeta (1-42) and stabilized the oligomerization [29].

Enzymatic interactions of HMGB1

• Surprisingly, in the course of these studies we found that in vivo radiolabeling experiments revealed that only two minor HMG-14 subspecies (and/or possibly a minor HMG-I subspecies) are phosphorylated whereas HMG-1, -2, -17, and the major HMG-14 are not heavily phosphorylated [30].
• These results indicate that casein kinase II is the enzyme which catalyzes the major phosphorylation of hHMG protein which occurs in vivo [31].

Regulatory relationships of HMGB1

• Similarly, in primary human macrophages, HMGB1-induced TNF release is dose-dependently inhibited by anti-TLR4 antibodies [32].
• Using EMSAs, both HMGB proteins are shown to enhance ER binding and induce cooperative ER binding on tandem ERE elements [33].
• In addition, the HMGB1-induced migration of EPCs on fibronectin and fibrinogen was significantly inhibited by antibodies against beta1 and beta2 integrins, respectively [24].
• In an in vitro transcription assay reconstituted with highly purified or recombinant general factors, HMG1 is able to inhibit transcription by RNA polymerase II over 30-fold [34].
• CONCLUSION: HMGB-1 was more strongly expressed in SF of RA patients than in that of OA patients, inducing the release of proinflammatory cytokines from SFMs [35].

Other interactions of HMGB1

• Finally, using transient transfection assays we show that HMG-1 can increase p53 and p53Delta30-mediated transactivation in vivo [36].
• In transient-transfection assays, coexpression of HMG-1 or HMG-2 increased PR-mediated transcription in mammalian cells by as much as 7- to 10-fold without altering the basal promoter activity of target reporter genes [37].
• The phosphorylation sites have been mapped to the acidic C-terminal domains by analysis of tryptic peptides derived from HMGB1 and HMGB2/3 using nanospray ion trap mass spectrometry [38].
• Double-stranded oligonucleotides containing the AG*G*C sequence, where the asterisks denote the sites of platination, with different spectator ligands are only moderately discriminated by the HMGB proteins and TBP, but the recognition of dsTG*G*A is highly dependent on the ligands [12].
• We thus explored the possibility that HMGB1 preconditioning was mediated through TLR4 activation [3].

Analytical, diagnostic and therapeutic context of HMGB1

• The overexpression of HMGB1 was further supported by Western blot analysis, and directly related to matrix metalloproteinase 2 overexpression [2].
• Electrophoretic mobility shift assays show that both the A and B domains of HMGB1 as well as TBP discriminate between different platinum-DNA adducts [12].
• Although this protein was not detected in the plasma of control humans or mice, the concentrations of HMGB1 in lung epithelial lining fluid or in bronchoalveolar lavage fluid were unexpectedly high [39].
• We found that serum/plasma components bind to HMGB1 and interfere with its detection by ELISA systems [40].
• Here, we describe sensitive ELISAs for the detection of HMGB1 in cell culture medium and cell lysates [40].

References