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Mitochondrial Stress and Cellular Senescence
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Irene L. Tan, Michael C. Velarde
High mobility group box (HMGB1) proteins regulate gene expression by bending DNA to allow transcription factors to bind to promoter regions (Davalos et al. 2013). However, during cellular damage, the HMGB1 protein is released from the nucleus in a p53-dependent manner and activates nuclear factor-κB (NF-κB) and other proinflammatory pathways to signal tissue damage (Davalos et al. 2013; Nacarelli, Liu, and Zhang 2017). MiDAS is associated with secretion of HMGB1 protein similar to the senescent phenotype induced by SIS (Wiley et al. 2016). Cells induced to senesce by exposure to X-ray radiation, overexpression of Ras oncogene, upregulation of the p16INK4a tumor suppressor, or repetitive culture also show HMGB1 secretion (Davalos et al. 2013).
Nonhistone Nuclear Phosphoproteins
Published in Lubomir S. Hnilica, Chromosomal Nonhistone Proteins, 2018
The high mobility group (HMG) of proteins is a subclass of nonhistone proteins defined by their extractability from chromatin by 0.35 M NaCl, their solubility in 2% TCA, and their relatively high electrophoretic mobility.86 Four major proteins (HMG-1, 2, 14, and 17) are present in this group.87 Isolated nucleosomes contain HMG proteins,87,88 and HMG 14 and 17 are associated with transcriptionally active or DNase I-sensitive regions of chromatin.89,90
Polynuclear Platinum Drugs
Published in Astrid Sigel, Helmut Sigel, Metal Ions in Biological Systems, 2004
As the understanding of the cellular mechanism of anticancer activity by drugs has progressed, it is clear that it is not Pt-DNA adducts per se which are responsible for the cytotoxicity but rather the effect these cellular signals have on downstream effects such as protein recognition, cell cycle arrest and especially DNA repair which dictates cellular response to any (drug) insult. In principle, if genuinely different biological activity is due to a different pattern of cellular responses then these should be observable as differential protein recognition. It is therefore of interest to examine the recognition by high mobility group proteins because of the structural information available on the cisplatin case and the comparisons that can be made. The survey has shown that these proteins do not recognize to any great extent the polynuclear platinum adducts. Logically, whatever role these proteins may play in mediating cisplatin toxicity is irrelevant in the case of I and II. HMG-domain proteins are only one of a host of proteins which recognize the bending motif of cisplatin - as a corrolary the polynuclear platinum adduct structures may not serve as substrate for other proteins with affinity for the DNA bending motif.
Role of RAGE and its ligand HMGB1 in the development of COPD
Published in Postgraduate Medicine, 2022
Lin Chen, Xuejiao Sun, Xiaoning Zhong
RAGE can bind to several endogenous DAMPs and activate immune and pro-inflammatory cascades by activating multiple signaling pathways, which are critical to the development of COPD [7]. RAGE is characterized by sustained activation of the pro-inflammatory transcription factor NF-κB induced by endogenous positive feedback loops, thus transforming a transient pro-inflammatory response into a long-term cellular dysfunction [7]. HMGB1 belongs to the high mobility group box protein family which is a protein motifs involved in DNA-binding [12]. HMGB1 is also the most widely studied DAMP and the ligand with the strongest affinity to RAGE [22]. The function of HMGB1 is related to its subcellular location and redox state. In the nucleus, HMGB1 is involved in many physiological processes such as DNA transcription, replication, and repair; in the cytoplasm, it activates inflammasome and autophagy; while on the extracellular space it binds and activates RAGE and Toll-like receptors 2/4 (TLR) receptors, which are critical to innate and acquired immunity [12,53]. The function of extracellular HMGB1 is related to its redox state. The reduced form of HMGB1 has chemotaxis properties, the disulfide form has pro-inflammatory activity, and the oxidized form is inactive [54]. The following sections will focus on the pathogenic role of extracellular HMGB1 in COPD.
Role of platelets and megakaryocytes in adaptive immunity
Published in Platelets, 2021
Genevieve Marcoux, Audrée Laroche, Jenifer Espinoza Romero, Eric Boilard
Activated platelets also release EVs. Platelet EVs are the most abundant EV in the bloodstream, representing approximately 80% of circulating EVs [169]. Platelet EVs are suggested to play numerous roles in regulating both physiological and pathological functions [170]. Platelet EVs can interact with lymphocytes and regulate regulatory T cell differentiation and activity [171,172]. Moreover, they can promote the formation of germinal centers and the production of IgG by B-cells as a function of their CD40L load [173,174]. As platelet EVs can circulate in lymph [175,176], they may be able to transport adaptive immunity molecules to lymphoid organs through this circulatory system. In autoimmune disease implicating IC, platelet EVs are shown to harbor autoantigens such as non-histone nuclear protein high mobility group box 1 (HMGB1) and citrullinated proteins (e.g. vimentin and fibrinogen) that are the targets of prevalent antibodies in SLE and rheumatoid arthritis [177,178]. Whether FcγRIIA can remain exposed on certain platelet EVs to contribute to dissemination of IC in these pathologies is not known. Future studies are necessary to highlight whether platelet EVs play roles in adaptive immunity, similarly to platelets and MK.
Targeting the intrinsically disordered architectural High Mobility Group A (HMGA) oncoproteins in breast cancer: learning from the past to design future strategies
Published in Expert Opinion on Therapeutic Targets, 2020
Silvia Pegoraro, Gloria Ros, Michela Sgubin, Sara Petrosino, Alberto Zambelli, Riccardo Sgarra, Guidalberto Manfioletti
High mobility group A (HMGA) proteins are non-histone nuclear proteins involved in gene expression regulation during embryogenesis and neoplastic transformation, where they are highly expressed, although they are almost undetectable in most adult tissues [reviewed within [1–4]]. This family includes two paralogous functional members: the HMGA1 and the HMGA2 genes that encode the HMGA1a and HMGA1b proteins, produced through alternative splicing, and the highly related HMGA2 protein, respectively [5]. These proteins are characterized by three highly conserved palindromic motifs (Pro-Arg-Gly-Arg-Pro), defined as ‘AT-hooks’, that bind to the minor groove of A/T rich B-form DNA sequences and an acidic C-terminal tail involved in the modulation of HMGA protein activities [reviewed within [1,3,6]]. Although these factors have no transcriptional activity per se, they contribute to gene expression regulation as chromatin architectural factors, altering the general chromatin status, competing with histone H1, interacting with transcription factors (TFs), and the transcription machinery [reviewed within [4]]. HMGA proteins bind to DNA and TFs, leading to the formation of stereospecific macromolecular complexes called ‘enhanceosomes’, which are crucial in transcription activation [7]. In addition to the role of HMGA proteins in gene transcription regulation, their involvement in other molecular processes, such as DNA repair [reviewed within [8]], DNA replication [9,10], chromatin structure [8,11], and RNA processing [12], is well established.