Role of the high mobility group A proteins in human lipomas

The high-mobility group A (HMGA) family of proteins orchestrates the assembly of nucleoprotein structures playing important roles in gene transcription, recombination, and chromatin structure through a complex network of protein–DNA and protein–protein interactions. Recently, we have generated transgenic mice carrying wild type or truncated HMGA2 genes under the transcriptional control of the cytomegalovirus promoter. These mice developed pituitary adenomas secreting prolactin and GH mainly due to an increased E2F1 activity, directly consequent to the HMGA2 overexpression. To identify other genes involved in the process of pituitary tumorigenesis induced by the HMGA2 gene, in this study we have analyzed the gene expression profile of three HMGA2-pituitary adenomas in comparison with a pool of ten normal pituitary glands from control mice, using the Affymetrix MG MU11K oligonucleotide array representing ~13 000 unique genes. We have identified 82 transcripts that increased and 72 transcripts that decreased at least four-fold in all the mice pituitary adenomas analyzed compared with normal pituitary glands. Among these genes, we focused our attention on the Mia/Cd-rap gene, whose expression was essentially suppressed in all of the pituitary adenomas tested by the microarray. We demonstrated that the HMGA proteins directly bind to the promoter of the Mia/Cd-rap gene and are able to downregulate its expression. In order to understand a possible role of Mia/Cd-rap in pituitary cell growth, we performed a colony assay in GH3 and GH4 cells. Interestingly, Mia/Cd-rap expression inhibits their proliferation, suggesting a potential tumor suppressor role of Mia/Cd-rap in pituitary cells.

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Role of the high mobility group A proteins in the regulation of pituitary cell cycle

Journal of Molecular Endocrinology ◽

10.1677/jme-09-0178 ◽

2010 ◽

Vol 44 (6) ◽

pp. 309-318 ◽

Cited By ~ 19

Author(s):

Monica Fedele ◽

Alfredo Fusco

Keyword(s):

Cell Cycle ◽

Pituitary Adenomas ◽

High Mobility ◽

High Mobility Group ◽

Tumor Evolution ◽

Pituitary Cells ◽

Pituitary Tumorigenesis ◽

Human Pathology ◽

Group A

Pituitary cells are particularly sensitive to alterations of the cell cycle machinery. In fact, mutations affecting expression of proteins critical for cell cycle progression, including retinoblastoma protein, cyclins D1 and D3, p16INK4A, and p27kip1, are frequent in human pituitary adenomas. Similarly, both targeted disruption and overexpression of either cell cycle inhibitors or activators, respectively, lead to the development of pituitary adenomas in mice. Recent evidence has added the high mobility group A (HMGA) proteins as a new class of cell cycle regulators that play significant roles in the pathways that lead to pituitary tumor evolution in both humans and experimental animal models. Here, we first review the role of the cell cycle in pituitary tumorigenesis, as witnessed by human pathology and transgenic mice; and then, we focus on HMGA proteins and their cell cycle-related role in pituitary tumorigenesis.

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High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics

Current Drug Targets ◽

10.2174/1389450120666190618125100 ◽

2019 ◽

Vol 20 (14) ◽

pp. 1474-1485 ◽

Cited By ~ 15

Author(s):

Eyaldeva C. Vijayakumar ◽

Lokesh Kumar Bhatt ◽

Kedar S. Prabhavalkar

Keyword(s):

Myocardial Infarction ◽

Vagus Nerve Stimulation ◽

Nuclear Protein ◽

Therapeutic Potential ◽

High Mobility ◽

Dna Binding Protein ◽

High Mobility Group ◽

Eukaryotic Cells ◽

Hmgb1 Protein

High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.

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Discovering high mobility group A molecular partners in tumour cells

PROTEOMICS ◽

10.1002/pmic.200401028 ◽

2005 ◽

Vol 5 (6) ◽

pp. 1494-1506 ◽

Cited By ~ 31

Author(s):

Riccardo Sgarra ◽

Michela A. Tessari ◽

Julie Di Bernardo ◽

Alessandra Rustighi ◽

Paola Zago ◽

...

Keyword(s):

High Mobility ◽

Tumour Cells ◽

High Mobility Group ◽

Group A

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Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes

Scientific Reports ◽

10.1038/s41598-021-88970-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hongseok Yoo ◽

Yunjoo Im ◽

Ryoung-Eun Ko ◽

Jin Young Lee ◽

Junseon Park ◽

...

Keyword(s):

Plasma Levels ◽

Validation Cohort ◽

High Mobility ◽

Kinase Domain ◽

High Mobility Group ◽

Rank Test ◽

Enzyme Linked Immunosorbent Assay ◽

Derivation Cohort ◽

The Difference

AbstractThe role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.

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LPS Primes Brain Responsiveness to High Mobility Group Box-1 Protein

Pharmaceuticals ◽

10.3390/ph14060558 ◽

2021 ◽

Vol 14 (6) ◽

pp. 558

Author(s):

Verena Peek ◽

Lois M. Harden ◽

Jelena Damm ◽

Ferial Aslani ◽

Stephan Leisengang ◽

...

Keyword(s):

Inflammatory Responses ◽

Area Postrema ◽

High Mobility ◽

High Mobility Group ◽

Direct Access ◽

Significant Release ◽

Factor Α ◽

Culture Supernatants

High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood–brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms.

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