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HMG Proteins in Development and Disease
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HMG Proteins in Development and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 62433

Special Issue Editors

Dr. Riccardo Sgarra

E-Mail Website
Guest Editor
Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
Interests: High Mobility Group A (HMGA) proteins; chromatin; protein-protein interactions; post-translational modifications (PTMs); epigenetic; cancer; mass spectrometry; proteomic
Special Issues, Collections and Topics in MDPI journals
Dr. Sabrina Battista

E-Mail Website
Guest Editor
Istituto per l’Endocrinologia e l’Oncologia Sperimentale “G. Salvatore” (IEOS), CNR, 80131 Naples, Italy
Interests: stem cells; cancer stem cells; carcinogenesis; glioblastoma; high mobility group proteins; asymmetric division; diet; adipose tissue; obesity; differentiation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Manfioletti Guidalberto

E-Mail Website
Guest Editor
Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
Interests: high mobility group A (HMGA) proteins; chromatin; regulation of gene expression; protein–protein interactions; post-translational modifications (PTMs); epithelial–mesenchymal transition; proteomics; tumor microenvironment; breast cancer; metastasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The High Mobility Group (HMG) proteins are chromatin architectural proteins subdivided into three distinct superfamilies: HMGA, HMGB, and HMGN. Each of them has specific and unusual relaxed interaction properties that enable them to interact with different DNA/chromatin sites and several cellular factors. These properties make them relevant hubs in the cellular network; indeed, they have been demonstrated to be key factors in different processes such as transcriptional regulation, embryonic development, cell signalling, DNA repair, apoptosis, maintenance of stemness, and senescence. As a consequence, HMG deregulations and misexpression lead to the development of several diseases/pathologies such as cancer, inflammation, and metabolic-related disorders. Moreover, during the last decades HMG have been demonstrated to have also extra nuclear functions, and indeed they have been found to be present in the cytoplasm and to be secreted/released in the extracellular environment. These peculiarities have significantly enlarged their already huge impact on cellular biology.

This Special Issue of IJMS will focus on the role HMG proteins play in development and disease. Articles submitted can either be original works regarding HMG functional/structural insight or full reviews; however, we kindly encourage authors to provide short and highly focused reviews on specific and hot topics related to HMGA, HMGB, or HMGN proteins.

Dr. Riccardo Sgarra
Dr. Sabrina Battista
Prof. G. Manfioletti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • High Mobility Group proteins
  • chromatin architecture
  • signalling
  • regulatory networks
  • AT-hooks
  • HMG box
  • nucleosome binding domain

Published Papers (14 papers)

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Research

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14 pages, 4640 KiB  
Article
Non-Thermal Plasma Application in Tumor-Bearing Mice Induces Increase of Serum HMGB1
by Olga Troitskaya, Ekaterina Golubitskaya, Mikhail Biryukov, Mikhail Varlamov, Pavel Gugin, Elena Milakhina, Vladimir Richter, Irina Schweigert, Dmitry Zakrevsky and Olga Koval
Int. J. Mol. Sci. 2020, 21(14), 5128; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145128 - 20 Jul 2020
Cited by 19 | Viewed by 3105
Abstract
The application of cold atmospheric plasma (CAP) in cancer therapy could be one of the new anticancer strategies. In the current work, we used cold atmospheric plasma jet for the treatment of cultured cells and mice. We showed that CAP induced the death [...] Read more.
The application of cold atmospheric plasma (CAP) in cancer therapy could be one of the new anticancer strategies. In the current work, we used cold atmospheric plasma jet for the treatment of cultured cells and mice. We showed that CAP induced the death of MX−7 mouse rhabdomyosarcoma cells with the hallmarks of immunogenic cell death (ICD): calreticulin and heat shock protein 70 (HSP70) externalization and high-mobility group box 1 protein (HMGB1) release. The intensity of HMGB1 release after the CAP treatment correlated directly with the basal extracellular HMGB1 level. Releasing from dying cells, HMGB1 can act as a proinflammatory cytokine. Our in vivo study demonstrated that cold atmospheric plasma induces a short-term two-times increase in serum HMGB1 level only in tumor-bearing mice with no effect in healthy mice. These findings support our hypothesis that CAP-dependent HMGB1 release from dying cancer cells can change the serum HMGB1 level. At the same time, we showed a weak cytokine response to CAP irradiation in healthy mice that can characterize CAP as an immune-safety physical antitumor approach. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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16 pages, 2292 KiB  
Article
High-Mobility Group Box 1 Protein Signaling in Painful Diabetic Neuropathy
by Vikram Thakur, Jayanarayanan Sadanandan and Munmun Chattopadhyay
Int. J. Mol. Sci. 2020, 21(3), 881; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030881 - 30 Jan 2020
Cited by 42 | Viewed by 4396
Abstract
Diabetes is a global epidemic and more than 50% diabetic patients are also diagnosed with neuropathy, which greatly affects the quality of life of the patients. Available treatments are not always successful due to the limited efficacy and complications, such as addiction and [...] Read more.
Diabetes is a global epidemic and more than 50% diabetic patients are also diagnosed with neuropathy, which greatly affects the quality of life of the patients. Available treatments are not always successful due to the limited efficacy and complications, such as addiction and dependency. Studies have implicated that high mobility group box1 (HMGB1) protein plays a crucial role in neuroinflammation and the development of neuropathic conditions. HMGB1 is a proinflammatory cytokine that can be released from necrotic cells in passive form or in response to inflammatory signals as an active form. HMGB1 is the ligand for the receptor for advanced glycation end products (RAGE), and toll-like receptors, (TLR)-2 and TLR4, which also indirectly activates C-X-C chemokine receptor type 4 (CXCR4). We investigated whether blocking of HMGB1 can reduce pain and inflammation in diabetic neuropathic animals to further understand the role of HMGB1 in diabetic neuropathy. Type 2 diabetic rats and mice were treated with natural inhibitor of HMGB1, glycyrrhizin (GLC) for five days/week for four weeks at a dose of 50 mg/kg per day by intraperitoneal injection. The animals were divided into three categories: naïve control, diabetic alone, diabetic with GLC treatment. All of the behavioral analyses were conducted before and after the treatment. The expression of inflammatory markers and changes in histone acetylation in the peripheral nervous system were measured by immunohistochemistry and Western blot analysis after the completion of the treatment. Our study revealed that TLR4, HMGB1, CXCR4, and Nod-like receptor protein 3 (NLRP3) levels were increased in the spinal and dorsal root ganglia (DRG) neurons of Type 2 diabetic mice and rats with painful neuropathy. GLC treatment inhibited the increases in TLR4, NLRP3, and CXCR4 expressions and improved the mechanical and thermal pain threshold in these animals. Immunohistochemical studies revealed that hyperglycemia mediated inflammation influenced HMGB1 acetylation and its release from the neurons. It also altered histone 3 acetylation in the microglial cells. The inhibition of HMGB1 by GLC prevented the release of HMGB1 as well as H3K9 acetylation. These findings indicate that the interruption of HMGB1 mediated inflammation could ameliorate diabetic neuropathy and might exhibit a unique target for the treatment. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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20 pages, 3746 KiB  
Article
High Mobility Group Box 1 and TLR4 Signaling Pathway in Gnotobiotic Piglets Colonized/Infected with L. amylovorus, L. mucosae, E. coli Nissle 1917 and S. Typhimurium
by Igor Splichal, Sharon M. Donovan, Vera Jenistova, Iva Splichalova, Hana Salmonova, Eva Vlkova, Vera Neuzil Bunesova, Marek Sinkora, Jiri Killer, Eva Skrivanova and Alla Splichalova
Int. J. Mol. Sci. 2019, 20(24), 6294; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246294 - 13 Dec 2019
Cited by 15 | Viewed by 2776
Abstract
High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein that can be actively secreted by immune cells after different immune stimuli or passively released from cells undergoing necrosis. HMGB1 amplifies inflammation, and its hypersecretion contributes to multiple organ dysfunction syndrome and [...] Read more.
High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein that can be actively secreted by immune cells after different immune stimuli or passively released from cells undergoing necrosis. HMGB1 amplifies inflammation, and its hypersecretion contributes to multiple organ dysfunction syndrome and death. We tested possible immunomodulatory effect of commensal Lactobacillus amylovorus (LA), Lactobacillus mucosae (LM) or probiotic Escherichia coli Nissle 1917 (EcN) in infection of gnotobiotic piglets with Salmonella Typhimurium (ST). Transcription of HMGB1 and Toll-like receptors (TLR) 2, 4, and 9 and receptor for advanced glycation end products (RAGE), TLR4-related molecules (MD-2, CD14, and LBP), and adaptor proteins (MyD88 and TRIF) in the ileum and colon were measured by RT-qPCR. Expression of TLR4 and its related molecules were highly upregulated in the ST-infected intestine, which was suppressed by EcN, but not LA nor LM. In contrast, HMGB1 expression was unaffected by ST infection or commensal/probiotic administration. HMGB1 protein levels in the intestine measured by ELISA were increased in ST-infected piglets, but they were decreased by previous colonization with E. coli Nissle 1917 only. We conclude that the stability of HMGB1 mRNA expression in all piglet groups could show its importance for DNA transcription and physiological cell functions. The presence of HMGB1 protein in the intestinal lumen probably indicates cellular damage. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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17 pages, 3665 KiB  
Article
The High Mobility Group A1 (HMGA1) Chromatin Architectural Factor Modulates Nuclear Stiffness in Breast Cancer Cells
by Beatrice Senigagliesi, Carlotta Penzo, Luisa Ulloa Severino, Riccardo Maraspini, Sara Petrosino, Hernan Morales-Navarrete, Enrico Pobega, Elena Ambrosetti, Pietro Parisse, Silvia Pegoraro, Guidalberto Manfioletti, Loredana Casalis and Riccardo Sgarra
Int. J. Mol. Sci. 2019, 20(11), 2733; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20112733 - 04 Jun 2019
Cited by 21 | Viewed by 4600
Abstract
Plasticity is an essential condition for cancer cells to invade surrounding tissues. The nucleus is the most rigid cellular organelle and it undergoes substantial deformations to get through environmental constrictions. Nuclear stiffness mostly depends on the nuclear lamina and chromatin, which in turn [...] Read more.
Plasticity is an essential condition for cancer cells to invade surrounding tissues. The nucleus is the most rigid cellular organelle and it undergoes substantial deformations to get through environmental constrictions. Nuclear stiffness mostly depends on the nuclear lamina and chromatin, which in turn might be affected by nuclear architectural proteins. Among these is the HMGA1 (High Mobility Group A1) protein, a factor that plays a causal role in neoplastic transformation and that is able to disentangle heterochromatic domains by H1 displacement. Here we made use of atomic force microscopy to analyze the stiffness of breast cancer cellular models in which we modulated HMGA1 expression to investigate its role in regulating nuclear plasticity. Since histone H1 is the main modulator of chromatin structure and HMGA1 is a well-established histone H1 competitor, we correlated HMGA1 expression and cellular stiffness with histone H1 expression level, post-translational modifications, and nuclear distribution. Our results showed that HMGA1 expression level correlates with nuclear stiffness, is associated to histone H1 phosphorylation status, and alters both histone H1 chromatin distribution and expression. These data suggest that HMGA1 might promote chromatin relaxation through a histone H1-mediated mechanism strongly impacting on the invasiveness of cancer cells. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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Review

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16 pages, 1534 KiB  
Review
The Mammalian High Mobility Group Protein AT-Hook 2 (HMGA2): Biochemical and Biophysical Properties, and Its Association with Adipogenesis
by Linjia Su, Zifang Deng and Fenfei Leng
Int. J. Mol. Sci. 2020, 21(10), 3710; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103710 - 25 May 2020
Cited by 19 | Viewed by 3944
Abstract
The mammalian high-mobility-group protein AT-hook 2 (HMGA2) is a small DNA-binding protein and consists of three “AT-hook” DNA-binding motifs and a negatively charged C-terminal motif. It is a multifunctional nuclear protein directly linked to obesity, human height, stem cell youth, human intelligence, and [...] Read more.
The mammalian high-mobility-group protein AT-hook 2 (HMGA2) is a small DNA-binding protein and consists of three “AT-hook” DNA-binding motifs and a negatively charged C-terminal motif. It is a multifunctional nuclear protein directly linked to obesity, human height, stem cell youth, human intelligence, and tumorigenesis. Biochemical and biophysical studies showed that HMGA2 is an intrinsically disordered protein (IDP) and could form homodimers in aqueous buffer solution. The “AT-hook” DNA-binding motifs specifically bind to the minor groove of AT-rich DNA sequences and induce DNA-bending. HMGA2 plays an important role in adipogenesis most likely through stimulating the proliferative expansion of preadipocytes and also through regulating the expression of transcriptional factor Peroxisome proliferator-activated receptor γ (PPARγ) at the clonal expansion step from preadipocytes to adipocytes. Current evidence suggests that a main function of HMGA2 is to maintain stemness and renewal capacity of stem cells by which HMGA2 binds to chromosome and lock chromosome into a specific state, to allow the human embryonic stem cells to maintain their stem cell potency. Due to the importance of HMGA2 in adipogenesis and tumorigenesis, HMGA2 is considered a potential therapeutic target for anticancer and anti-obesity drugs. Efforts are taken to identify inhibitors targeting HMGA2. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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23 pages, 975 KiB  
Review
High Mobility Group AT-Hook 2 (HMGA2) Oncogenicity in Mesenchymal and Epithelial Neoplasia
by Uchenna Unachukwu, Kiran Chada and Jeanine D’Armiento
Int. J. Mol. Sci. 2020, 21(9), 3151; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093151 - 29 Apr 2020
Cited by 32 | Viewed by 3464
Abstract
High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding [...] Read more.
High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding of HMGA2 pathogenicity by exploring the mechanisms by which HMGA2 misexpression and ectopic expression induces mesenchymal and epithelial tumorigenesis respectively and distinguish the pathogenesis of benign from malignant mesenchymal tumors. Importantly, we highlight the regulatory role of let-7 microRNA family of tumor suppressors in determining HMGA2 misexpression events leading to tumor pathogenesis and focused on possible mechanisms by which HMGA2 could propagate lymphangioleiomyomatosis (LAM), benign mesenchymal tumors of the lungs. Lastly, we discuss potential therapeutic strategies for epithelial and mesenchymal tumorigenesis based on targeting the HMGA2 signaling pathway. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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14 pages, 653 KiB  
Review
Targeting High Mobility Group Box 1 in Subarachnoid Hemorrhage: A Systematic Review
by Sajjad Muhammad, Shafqat Rasul Chaudhry, Ulf Dietrich Kahlert, Martin Lehecka, Miikka Korja, Mika Niemelä and Daniel Hänggi
Int. J. Mol. Sci. 2020, 21(8), 2709; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082709 - 14 Apr 2020
Cited by 20 | Viewed by 5529
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) is a complex and potentially deadly disease. Neurosurgical clipping or endovascular coiling can successfully obliterate ruptured aneurysms in almost every case. However, despite successful interventions, the clinical outcomes of aSAH patients are often poor. The reasons for poor outcomes [...] Read more.
Aneurysmal subarachnoid hemorrhage (aSAH) is a complex and potentially deadly disease. Neurosurgical clipping or endovascular coiling can successfully obliterate ruptured aneurysms in almost every case. However, despite successful interventions, the clinical outcomes of aSAH patients are often poor. The reasons for poor outcomes are numerous, including cerebral vasospasm (CVS), post-hemorrhagic hydrocephalus, systemic infections and delayed cerebral ischemia. Although CVS with subsequent cerebral ischemia is one of the main contributors to brain damage after aSAH, little is known about the underlying molecular mechanisms of brain damage. This review emphasizes the importance of pharmacological interventions targeting high mobility group box 1 (HMGB1)-mediated brain damage after subarachnoid hemorrhage (SAH) and CVS. We searched Pubmed, Ovid medline and Scopus for “subarachnoid hemorrhage” in combination with “HMGB1”. Based on these criteria, a total of 31 articles were retrieved. After excluding duplicates and selecting the relevant references from the retrieved articles, eight publications were selected for the review of the pharmacological interventions targeting HMGB1 in SAH. Damaged central nervous system cells release damage-associated molecular pattern molecules (DAMPs) that are important for initiating, driving and sustaining the inflammatory response following an aSAH. The discussed evidence suggested that HMGB1, an important DAMP, contributes to brain damage during early brain injury and also to the development of CVS during the late phase. Different pharmacological interventions employing natural compounds with HMGB1-antagonizing activity, antibody targeting of HMGB1 or scavenging HMGB1 by soluble receptors for advanced glycation end products (sRAGE), have been shown to dampen the inflammation mediated brain damage and protect against CVS. The experimental data suggest that HMGB1 inhibition is a promising strategy to reduce aSAH-related brain damage and CVS. Clinical studies are needed to validate these findings that may lead to the development of potential treatment options that are much needed in aSAH. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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30 pages, 2569 KiB  
Review
High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network
by Riccardo Sgarra, Silvia Pegoraro, Daniela D’Angelo, Gloria Ros, Rossella Zanin, Michela Sgubin, Sara Petrosino, Sabrina Battista and Guidalberto Manfioletti
Int. J. Mol. Sci. 2020, 21(3), 717; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030717 - 22 Jan 2020
Cited by 6 | Viewed by 3543
Abstract
High mobility group A (HMGA) proteins are oncofoetal chromatin architectural factors that are widely involved in regulating gene expression. These proteins are unique, because they are highly expressed in embryonic and cancer cells, where they play a relevant role in cell proliferation, stemness, [...] Read more.
High mobility group A (HMGA) proteins are oncofoetal chromatin architectural factors that are widely involved in regulating gene expression. These proteins are unique, because they are highly expressed in embryonic and cancer cells, where they play a relevant role in cell proliferation, stemness, and the acquisition of aggressive tumour traits, i.e., motility, invasiveness, and metastatic properties. The HMGA protein expression levels and activities are controlled by a connected set of events at the transcriptional, post-transcriptional, and post-translational levels. In fact, microRNA (miRNA)-mediated RNA stability is the most-studied mechanism of HMGA protein expression modulation. In this review, we contribute to a comprehensive overview of HMGA-targeting miRNAs; we provide detailed information regarding HMGA gene structural organization and a comprehensive evaluation and description of HMGA-targeting miRNAs, while focusing on those that are widely involved in HMGA regulation; and, we aim to offer insights into HMGA-miRNA mutual cross-talk from a functional and cancer-related perspective, highlighting possible clinical implications. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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39 pages, 2523 KiB  
Review
HMGA Genes and Proteins in Development and Evolution
by Robert Vignali and Silvia Marracci
Int. J. Mol. Sci. 2020, 21(2), 654; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020654 - 19 Jan 2020
Cited by 47 | Viewed by 5186
Abstract
HMGA (high mobility group A) (HMGA1 and HMGA2) are small non-histone proteins that can bind DNA and modify chromatin state, thus modulating the accessibility of regulatory factors to the DNA and contributing to the overall panorama of gene expression tuning. In general, they [...] Read more.
HMGA (high mobility group A) (HMGA1 and HMGA2) are small non-histone proteins that can bind DNA and modify chromatin state, thus modulating the accessibility of regulatory factors to the DNA and contributing to the overall panorama of gene expression tuning. In general, they are abundantly expressed during embryogenesis, but are downregulated in the adult differentiated tissues. In the present review, we summarize some aspects of their role during development, also dealing with relevant studies that have shed light on their functioning in cell biology and with emerging possible involvement of HMGA1 and HMGA2 in evolutionary biology. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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27 pages, 1571 KiB  
Review
Biological Functions of HMGN Chromosomal Proteins
by Ravikanth Nanduri, Takashi Furusawa and Michael Bustin
Int. J. Mol. Sci. 2020, 21(2), 449; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020449 - 10 Jan 2020
Cited by 23 | Viewed by 6485
Abstract
Chromatin plays a key role in regulating gene expression programs necessary for the orderly progress of development and for preventing changes in cell identity that can lead to disease. The high mobility group N (HMGN) is a family of nucleosome binding proteins that [...] Read more.
Chromatin plays a key role in regulating gene expression programs necessary for the orderly progress of development and for preventing changes in cell identity that can lead to disease. The high mobility group N (HMGN) is a family of nucleosome binding proteins that preferentially binds to chromatin regulatory sites including enhancers and promoters. HMGN proteins are ubiquitously expressed in all vertebrate cells potentially affecting chromatin function and epigenetic regulation in multiple cell types. Here, we review studies aimed at elucidating the biological function of HMGN proteins, focusing on their possible role in vertebrate development and the etiology of disease. The data indicate that changes in HMGN levels lead to cell type-specific phenotypes, suggesting that HMGN optimize epigenetic processes necessary for maintaining cell identity and for proper execution of specific cellular functions. This manuscript contains tables that can be used as a comprehensive resource for all the English written manuscripts describing research aimed at elucidating the biological function of the HMGN protein family. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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17 pages, 1364 KiB  
Review
HMGA Proteins in Stemness and Differentiation of Embryonic and Adult Stem Cells
by Silvia Parisi, Silvia Piscitelli, Fabiana Passaro and Tommaso Russo
Int. J. Mol. Sci. 2020, 21(1), 362; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010362 - 06 Jan 2020
Cited by 38 | Viewed by 5233
Abstract
HMGA1 and HMGA2 are chromatin architectural proteins that do not have transcriptional activity per se, but are able to modify chromatin structure by interacting with the transcriptional machinery and thus negatively or positively regulate the transcription of several genes. They have been extensively [...] Read more.
HMGA1 and HMGA2 are chromatin architectural proteins that do not have transcriptional activity per se, but are able to modify chromatin structure by interacting with the transcriptional machinery and thus negatively or positively regulate the transcription of several genes. They have been extensively studied in cancer where they are often found to be overexpressed but their functions under physiologic conditions have still not been completely addressed. Hmga1 and Hmga2 are expressed during the early stages of mouse development, whereas they are not detectable in most adult tissues. Hmga overexpression or knockout studies in mouse have pointed to a key function in the development of the embryo and of various tissues. HMGA proteins are expressed in embryonic stem cells and in some adult stem cells and numerous experimental data have indicated that they play a fundamental role in the maintenance of stemness and in the regulation of differentiation. In this review, we discuss available experimental data on HMGA1 and HMGA2 functions in governing embryonic and adult stem cell fate. Moreover, based on the available evidence, we will aim to outline how HMGA expression is regulated in different contexts and how these two proteins contribute to the regulation of gene expression and chromatin architecture in stem cells. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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24 pages, 923 KiB  
Review
High Mobility Group Box-1 and Diabetes Mellitus Complications: State of the Art and Future Perspectives
by Federico Biscetti, Maria Margherita Rando, Elisabetta Nardella, Andrea Leonardo Cecchini, Giovanni Pecorini, Raffaele Landolfi and Andrea Flex
Int. J. Mol. Sci. 2019, 20(24), 6258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246258 - 11 Dec 2019
Cited by 34 | Viewed by 4211
Abstract
Diabetes mellitus (DM) is an endemic disease, with growing health and social costs. The complications of diabetes can affect potentially all parts of the human body, from the heart to the kidneys, peripheral and central nervous system, and the vascular bed. Although many [...] Read more.
Diabetes mellitus (DM) is an endemic disease, with growing health and social costs. The complications of diabetes can affect potentially all parts of the human body, from the heart to the kidneys, peripheral and central nervous system, and the vascular bed. Although many mechanisms have been studied, not all players responsible for these complications have been defined yet. High Mobility Group Box-1 (HMGB1) is a non-histone nuclear protein that has been implicated in many pathological processes, from sepsis to ischemia. The purpose of this review is to take stock of all the most recent data available on the role of HMGB1 in the complications of DM. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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18 pages, 1202 KiB  
Review
Clinical Implications of Extracellular HMGA1 in Breast Cancer
by Olga Méndez, José Pérez, Jesus Soberino, Fabricio Racca, Javier Cortés and Josep Villanueva
Int. J. Mol. Sci. 2019, 20(23), 5950; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235950 - 26 Nov 2019
Cited by 19 | Viewed by 3470
Abstract
The unconventional secretion of proteins is generally caused by cellular stress. During the tumorigenesis, tumor cells experience high levels of stress, and the secretion of some theoretically intracellular proteins is activated. Once in the extracellular space, these proteins play different paracrine and autocrine [...] Read more.
The unconventional secretion of proteins is generally caused by cellular stress. During the tumorigenesis, tumor cells experience high levels of stress, and the secretion of some theoretically intracellular proteins is activated. Once in the extracellular space, these proteins play different paracrine and autocrine roles and could represent a vulnerability of cancer. One of these proteins is the high mobility group A1 (HMGA1), which is frequently overexpressed in tumors and presents a low expression in normal adult tissues. We have recently described that HMGA1 establishes an autocrine loop in invasive triple-negative breast cancer (TNBC) cells. The secretion of HMGA1 and its binding to the receptor for advanced glycation end products (RAGE) mediates the migration, invasion, and metastasis of TNBC cells and predicts the onset of metastasis in these patients. In this review, we summarized different strategies to exploit the novel tumorigenic phenotype mediated by extracellular HMGA1. We envisioned future clinical applications where the association between its change in subcellular localization and breast cancer progression could be used to predict tumor aggressiveness and guide treatment decisions. Furthermore, we proposed that targeting extracellular HMGA1 as monotherapy using monoclonal antibodies, or in combination with chemotherapy and other targeted therapies, could bring new therapeutic options for TNBC patients. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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17 pages, 1727 KiB  
Review
Role of High-Mobility Group Box-1 in Liver Pathogenesis
by Bilon Khambu, Shengmin Yan, Nazmul Huda and Xiao-Ming Yin
Int. J. Mol. Sci. 2019, 20(21), 5314; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215314 - 25 Oct 2019
Cited by 42 | Viewed by 5263
Abstract
High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA [...] Read more.
High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases. Full article
(This article belongs to the Special Issue HMG Proteins in Development and Disease)
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