Journal articles: 'HMGA proteins'

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Meireles Da Costa, Nathalia, Luis Felipe Ribeiro Pinto, Luiz Eurico Nasciutti, and Antonio Palumbo Jr. "The Prominent Role of HMGA Proteins in the Early Management of Gastrointestinal Cancers." BioMed Research International 2019 (October 13, 2019): 1–7. http://dx.doi.org/10.1155/2019/2059516.

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GI tumors represent a heterogeneous group of neoplasms concerning their natural history and molecular alterations harbored. Nevertheless, these tumors share very high incidence and mortality rates worldwide and patients’ poor prognosis. Therefore, the identification of specific biomarkers could increase the development of personalized medicine, in order to improve GI cancer management. In this sense, HMGA family members (HMGA1 and HMGA2) comprise an important group of genes involved in the genesis and progression of malignant tumors. Additionally, it has also been reported that HMGA1 and HMGA2 display an important role in the detection and progression of GI tumors. In this way, HMGA family members could be used as reliable biomarkers able to efficiently track not only the tumor per se but also the main risk conditions related with their development of GI cancers in the future. Finally, it shall be a promising option to revert the current scenario, once HMGA genes and proteins could represent a convergence point in the complex landscape of GI tumors.

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Parisi, Silvia, Silvia Piscitelli, Fabiana Passaro, and Tommaso Russo. "HMGA Proteins in Stemness and Differentiation of Embryonic and Adult Stem Cells." International Journal of Molecular Sciences 21, no. 1 (January 6, 2020): 362. http://dx.doi.org/10.3390/ijms21010362.

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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.

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Vignali, Robert, and Silvia Marracci. "HMGA Genes and Proteins in Development and Evolution." International Journal of Molecular Sciences 21, no. 2 (January 19, 2020): 654. http://dx.doi.org/10.3390/ijms21020654.

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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.

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PIERANTONI, Giovanna Maria, Valter AGOSTI, Monica FEDELE, Heather BOND, Irene CALIENDO, Gennaro CHIAPPETTA, Francesco LO COCO, et al. "High-mobility group A1 proteins are overexpressed in human leukaemias." Biochemical Journal 372, no. 1 (May 15, 2003): 145–50. http://dx.doi.org/10.1042/bj20021493.

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High-mobility group A (HMGA) proteins are non-histone nuclear proteins that bind DNA and several transcription factors. They are involved in the regulation of chromatin structure and function. HMGA protein expression is low in normal adult tissues, but abundant during embryonic development and in several human tumours. Rearrangements of the HMGA genes have been frequently detected in human benign tumours of mesenchymal origin, e.g. lipomas, lung hamartomas and uterine leiomiomas. HMGA proteins have been implicated in the control of cell growth and differentiation of the pre-adipocytic cell line 3T3-L1. In an attempt to better understand the role of HMGA1 proteins in haematological neoplasias and in the differentiation of haematopietic cells, we have investigated their expression in human leukaemias and in leukaemic cell lines induced to terminal differentiation. Here we report HMGA1 overexpression in most fresh human leukaemias of different origin and in several leukaemic cell lines. Moreover, differentiation of three cell lines towards the megakaryocytic phenotype was associated with HMGA1 protein induction, whereas induction of erythroid and monocytic differentiation generally resulted in reduced HMGA1 expression.

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Lichota, J., and K. D. Grasser. "Interaction of Maize Chromatin-Associated HMG Proteins with Mononucleosomes: Role of Core and Linker Histones." Biological Chemistry 384, no. 7 (July 15, 2003): 1019–27. http://dx.doi.org/10.1515/bc.2003.114.

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AbstractTwo groups of plant chromatin-associated high mobility group (HMG) proteins, namely the HMGA family, typically containing four A/T-hook DNA-binding motifs, and the HMGB family, containing a single HMG-box DNA-binding domain, have been identified. We have examined the interaction of recombinant maize HMGA and five different HMGB proteins with mononucleosomes (containing approx. 165 bp of DNA) purified from micrococcal nuclease-digested maize chromatin. The HMGB proteins interacted with the nucleosomes independent of the presence of the linker histone H1, while the binding of HMGA in the presence of H1 differed from that observed in the absence of H1. HMGA and the HMGB proteins bound H1-containing nucleosome particles with similar affinity. The plant HMG proteins could also bind nucleosomes that were briefly treated with trypsin (removing the N-terminal domains of the core histones), suggesting that the histone N-termini are dispensable for HMG protein binding. In the presence of untreated nucleosomes and trypsinised nucleosomes, HMGB1 could be chemically crosslinked with a core histone, which indicates that the trypsin-resistant part of the histones within the nucleosome is the main interaction partner of HMGB1 rather than the histone N-termini. In conclusion, these results indicate that specific nucleosome binding of the plant HMGB proteins requires simultaneous DNA and histone contacts.

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Balachandran, Akilandeswari, Ajit Zambre, Jagjot Singh Kainth, Lakshmi Dhevi Nagarajha Selvan, Sowmya Parameswaran, Zahra Afrasiabi, Subramanian Krishnakumar, Raghuraman Kannan, and Anandhi Upendran. "Targeting HMGA protein inhibits retinoblastoma cell proliferation." RSC Advances 8, no. 55 (2018): 31510–14. http://dx.doi.org/10.1039/c8ra06026f.

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Li, Liping, Wenyan Lu, Alison R. Moliterno, Lingling Xian, Joseph Kim, Ophelia Rogers, Jerry L. Spivak, and Linda Resar. "High Mobility Group A1 Chromatin Regulators: Key Epigenetic Switches and Therapeutic Targets Required for Leukemic Transformation in JAK2 Mutant MPN." Blood 134, Supplement_1 (November 13, 2019): 1680. http://dx.doi.org/10.1182/blood-2019-130262.

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Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by hyperactive JAK/STAT signaling and increased risk of transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). However, mechanisms driving progression remain elusive and therapies are ineffective after leukemia develops. The High Mobility Group A1/2 (HMGA1/2) genes encode oncogenic chromatin remodeling proteins which are overexpressed in aggressive solid tumors where they portend adverse outcomes. HMGA1/2 genes are also up-regulated in hematologic malignancies and MPN with disease progression. In murine models, Hmga1/2 overexpression drives clonal expansion and deregulated proliferation while Hmga1 overexpression is sufficient for lymphoid leukemic transformation. We therefore sought to: 1) test the hypothesis that HMGA1/2 proteins are rational therapeutic targets required for leukemic transformation in MPN, 2) elucidate mechanisms mediated by HMGA1/2 during disease progression, and, 3) identify therapeutic approaches to disrupt HMGA function and intercept the transition from chronic disease to aggressive leukemia. Methods: We compared HMGA1/2 in JAK2V617F mutant AML cell lines from MPN patients (DAMI, SET-2), CD34+ cells from PV patients during chronic and transformation phases, and JAK2V617F murine models of PV (transgenic JAK2V617F) and PV-AML (transgenic JAK2V617F/MPLSV). To elucidate HMGA1/2 function, we silenced HMGA1 or HMGA2 via short hairpin RNA in human MPN-AML cells and generated murine models of PV-AML with heterozygous Hmga1 or Hmga2 deficiency. To dissect molecular mechanisms underlying HMGA, we compared RNA-Seq from MPN-AML cell lines after gene silencing. Finally, to identify therapies to target HMGA pathways, we integrated the RNA-Seq data with the Broad Connectivity Map (cMAP). Results: There is a marked up-regulation in HMGA1/2 in CD34+ cells from PV patients after transformation to AML and in leukemic blasts from our PV-AML mouse model. Conversely, silencing HMGA1 or HMGA2 in human MPN-AML cell lines (DAMI, SET-2) dramatically halts proliferation, disrupts clonogenicity, and prevents leukemia development in mice. Further, heterozygous Hmga1 deficiency prolongs survival in the transgenic PV-AML murine model with fulminant leukemia and early mortality, although Hmga2 deficiency has no effect. RNA-Seq analyses from human MPN-AML cell lines revealed that HMGA1 up-regulates transcriptional networks involved in cell cycle progressions (E2F targets, mitotic spindle, G2M checkpoint, MYC targets) while repressing immune pathways (inflammation, interferon gamma) and oxidative phosphorylation. HMGA2 up-regulates similar pathways, but represses TNFalpha signaling. cMAP identified inhibitors of histone deacetylation and cell cycle progression as potential agents to target HMGA1 pathways; DNA synthesis inhibitors were predicted to target HMGA2 pathways. Cytotoxicity assays demonstrate that epigenetic therapy with HDAC inhibitors synergizes with Ruxolitinib in JAK2 mutant MPN cells after transformation to leukemia. Conclusions: HMGA1/2 genes are overexpressed in MPN with highest levels after leukemic transformation. Further, silencing HMGA1/2 disrupts leukemogenic phenotypes in vitro and prevents the development of leukemia in mice. In addition, heterozygous deficiency of Hmga1 prolongs survival in a fulminant MPN-AML model. Mechanistically, RNA-Seq analyses revealed that HMGA amplifies transcriptional networks involved cell cycle progression, which can be targeted with epigenetic therapies. Our findings further underscore the key role for HMGA as an epigenetic switch required for leukemic transformation in MPN and opens the door to novel therapeutic approaches to intercept the transition from chronic indolent disease to aggressive leukemia. Disclosures No relevant conflicts of interest to declare.

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Ismail, A. A., S. Wagner, H. Murua Escobar, S. Willenbrock, K. A. Sterenczak, M. T. Samy, A. M. Abd El-Aal, I. Nolte, and P. Wefstaedt. "Effects of High-Mobility Group A Protein Application on Canine Adipose-Derived Mesenchymal Stem CellsIn Vitro." Veterinary Medicine International 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/752083.

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Multipotency and self-renewal are considered as most important features of stem cells to persist throughout life in tissues. In this context, the role of HMGA proteins to influence proliferation of adipose-derived mesenchymal stem cell (ASCs) while maintaining their multipotent and self-renewal capacities has not yet been investigated. Therefore, extracellular HMGA1 and HMGA2 application alone (10–200 ng/mL) and in combination with each other (100, 200 ng/mL each) was investigated with regard to proliferative effects on canine ASCs (cASCs) after 48 hours of cultivation. Furthermore, mRNA expression of multipotency marker genes in unstimulated and HMGA2-stimulated cASCs (50, 100 ng/mL) was analyzed by RT-qPCR. HMGA1 significantly reduced cASCs proliferation in concentrations of 10–200 ng/mL culture medium. A combination of HMGA1 and HMGA2 protein (100 and 200 ng/mL each) caused the same effects, whereas no significant effect on cASCs proliferation was shown after HMGA2 protein application alone. RT-qPCR results showed that expression levels of marker genes including KLF4, SOX2, OCT4, HMGA2, and cMYC mRNAs were on the same level in both HMGA2-protein-stimulated and -unstimulated cASCs. Extracellular HMGA protein application might be valuable to control proliferation of cASCs in context with their employment in regenerative approaches without affecting their self-renewal and multipotency abilities.

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Fedele, Monica, Giovanna Maria Pierantoni, Pierlorenzo Pallante, and Alfredo Fusco. "High mobility group A-interacting proteins in cancer: focus on chromobox protein homolog 7, homeodomain interacting protein kinase 2 and PATZ." Journal of Nucleic Acids Investigation 3, no. 1 (March 16, 2012): 1. http://dx.doi.org/10.4081/jnai.2012.3988.

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The High Mobility Group A (HMGA) proteins, a family of DNA architectural factors, by interacting with different proteins play crucial roles in neoplastic transformation of a wide range of tissues. Therefore, the search for HMGA-interacting partners was carried out by several laboratories in order to investigate the mechanisms underlying HMGA-dependent tumorigenesis. Three of the several HMGA-binding proteins are discussed in this review. These are the Chromobox family protein (chromobox protein homolog 7, CBX7), the homeodomain interacting protein kinase 2 (HIPK2) and the POZ/domain and Kruppel zinc finger family member, PATZ. All of them play a critical role in tumorigenesis, and may also be independent markers of cancer. Their activities are linked to cell cycle, apoptosis and senescence. In this review, we discuss the properties of each protein, including their effect on HMGA1 functions, and propose a model accounting for how their activities might be coordinated.

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Resar, Linda, Donna Marie Williams, Zhizhuang Joe Zhao, Ophelia Rogers, Lingling Xian, Jerry L. Spivak, and Alison R. Moliterno. "High Mobility Group A1/2 Chromatin Remodeling Proteins Associate with Polycythemia Vera Transformation to Acute Leukemia in Humans and a JAK2 V617F Transgenic Mouse Model." Blood 128, no. 22 (December 2, 2016): 1958. http://dx.doi.org/10.1182/blood.v128.22.1958.1958.

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Abstract Introduction: The MPN are clonal hematopoietic stem cell (HSC) disorders characterized by an overproduction of blood cells and an increased risk of transformation to an aggressive phase with myelofibrosis (MF) and/or acute myeloid leukemia (AML). Polycythemia vera (PV) is the most common clinical subtype, and while PV starts as an indolent process, nearly 25% of patients will progress to MF and/or AML. PV is caused by acquired mutations of JAK2, yet JAK2 mutations alone do not account for MF or AML transformation. Mutations in genes encoding epigenetic regulators are associated with MPN transformation, but the mechanism of action is not understood. HMGA1/2 chromatin binding proteins are potent oncogenes that drive tumor progression by activating oncogenic and stem cell transcriptional networks. Both HMGA1/2 are overexpressed in acute leukemia and have been shown to be drivers of clonal expansion in myeloid disease in humans and in murine myeloproliferative disease models. We hypothesized that HMGA proteins could be critical drivers of transformation in PV and therefore tested the association of HMGA1/2 expression to transformation in human and murine PV. Methods: We examined the HSC genomic context and clonal evolution in 49 JAK2V617F-positive PV patients using standard and SNP-array karyotyping and a targeted resequencing panel of 163 genes associated with myeloid cancers. We examined HSC clonal burden by examining JAK2V617F HSC genotypes on a single cell basis. We measured HMGA1 and HMGA2 expression in a JAK2V617F positive human cell line, in isolated CD34+ HSCs from PV patients during chronic and transformation phases, in JAK2V617F transgenic murine models of PV (tgJAK2V617F) and PV-AML (tgJAK2V617F/MPLSV; Blood 2015;126:484) using a real-time quantitative RT-PCR (qRT-PCR) assay. Results: Both HMGA1 and HMGA2 mRNA were up-regulated in all JAK2V617F-positive contexts. In primary human PV CD34+ HSCs, HMGA1 and HMGA2 were found to be increased by 7 and 100 fold, respectively, compared to controls. Moreover, there was a dramatic up-regulation in both HMGA1/2 in patients who transformed from PV to MF or AML compared to chronic phase PV, whether analyzed cross-sectionally (Figure) or prospectively in selected patients. In addition to disease phase, over-expression of HMGA1/2 correlated with clonal dominance of JAK2V617F-homozygous stem cells, and additional mutations of epigenetic regulators including EZH2 and SETBP1. Similarly, when assessed in unfractionated bone marrow or in tumor samples in the two transgenic mouse models for PV and PV-AML, Hmga1/2 were overexpressed compared to wild-type littermates, with highest levels in the PV-AML transgenic mouse model. Conclusion: HMGA1 and HMGA2 are overexpressed in PV, and higher levels associate with disease progression to MF and AML, both in human PV and in transgenic murine models of PV. These data suggest HMGA proteins are critical drivers of PV transformation and that the mechanism of HMGA1/2 overexpression is a consequence of aberrant JAK/STAT signaling and epigenetic dysregulation. Our findings indicate that HMGA1/2 overexpression may function as a necessary molecular switch for PV leukemic transformation. Therefore, HMGA proteins and their transcriptional pathways offer novel therapeutic targets aimed at the prevention of PV progression to MF and AML. Disclosures No relevant conflicts of interest to declare.

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Palmieri, Dario, Teresa Valentino, Ivana De Martino, Francesco Esposito, Paolo Cappabianca, Anne Wierinckx, Michela Vitiello, et al. "PIT1 upregulation by HMGA proteins has a role in pituitary tumorigenesis." Endocrine-Related Cancer 19, no. 2 (December 23, 2011): 123–35. http://dx.doi.org/10.1530/erc-11-0135.

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We have previously demonstrated that HMGA1B and HMGA2 overexpression in mice induces the development of GH and prolactin (PRL) pituitary adenomas mainly by increasing E2F1 transcriptional activity. Interestingly, these adenomas showed very high expression levels of PIT1, a transcriptional factor that regulates the gene expression ofGh,Prl,GhrhrandPit1itself, playing a key role in pituitary gland development and physiology. Therefore, the aim of our study was to identify the role ofPit1overexpression in pituitary tumour development induced by HMGA1B and HMGA2. First, we demonstrated that HMGA1B and HMGA2 directly interact with both PIT1 and its gene promoterin vivo, and that these proteins positively regulatePit1promoter activity, also co-operating with PIT1 itself. Subsequently, we showed, by colony-forming assays on two different pituitary adenoma cell lines, GH3 and αT3, thatPit1overexpression increases pituitary cell proliferation. Finally, the expression analysis ofHMGA1,HMGA2andPIT1in human pituitary adenomas of different histological types revealed a direct correlation betweenPIT1and HMGA expression levels. Taken together, our data indicate a role ofPit1upregulation by HMGA proteins in pituitary tumours.

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Tessari, Michela A., Monica Gostissa, Sandro Altamura, Riccardo Sgarra, Alessandra Rustighi, Clio Salvagno, Giuseppina Caretti, et al. "Transcriptional Activation of the Cyclin A Gene by the Architectural Transcription Factor HMGA2." Molecular and Cellular Biology 23, no. 24 (December 15, 2003): 9104–16. http://dx.doi.org/10.1128/mcb.23.24.9104-9116.2003.

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ABSTRACT The HMGA2 protein belongs to the HMGA family of architectural transcription factors, which play an important role in chromatin organization. HMGA proteins are overexpressed in several experimental and human tumors and have been implicated in the process of neoplastic transformation. Hmga2 knockout results in the pygmy phenotype in mice and in a decreased growth rate of embryonic fibroblasts, thus indicating a role for HMGA2 in cell proliferation. Here we show that HMGA2 associates with the E1A-regulated transcriptional repressor p120E4F, interfering with p120E4F binding to the cyclin A promoter. Ectopic expression of HMGA2 results in the activation of the cyclin A promoter and induction of the endogenous cyclin A gene. In addition, chromatin immunoprecipitation experiments show that HMGA2 associates with the cyclin A promoter only when the gene is transcriptionally activated. These data identify the cyclin A gene as a cellular target for HMGA2 and, for the first time, suggest a mechanism for HMGA2-dependent cell cycle regulation.

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De Martino, Marco, Alfredo Fusco, and Francesco Esposito. "HMGA and Cancer: A Review on Patent Literatures." Recent Patents on Anti-Cancer Drug Discovery 14, no. 3 (November 21, 2019): 258–67. http://dx.doi.org/10.2174/1574892814666190919152001.

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Background: The high mobility group A proteins modulate the transcription of numerous genes by interacting with transcription factors and/or altering the structure of chromatin. These proteins are involved in both benign and malignant neoplasias as a result of several pathways. A large amount of benign human mesenchymal tumors has rearrangements of HMGA genes. On the contrary, malignant tumors show unarranged HMGA overexpression that is frequently and causally related to neoplastic cell transformation. Here, we review the function of the HMGA proteins in human neoplastic disorders, the pathways by which they contribute to carcinogenesis and the new patents focused on targeting HMGA proteins. Objective: Current review was conducted to check the involvement of HMGA as a druggable target in cancer treatment. Methods: We reviewed the most recent patents focused on targeting HMGA in cancer treatment analyzing patent literature published during the last years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. Results: HMGA proteins are intriguing targets for cancer therapy and are objects of different patents based on the use of DNA aptamers, inhibitors, oncolytic viruses, antisense molecules able to block their oncogenic functions. Conclusion: Powerful strategies able to selectively interfere with HMGA expression and function could represent a helpful approach in the development of new anti-cancer therapies.

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Sgarra, Riccardo, Silvia Pegoraro, Daniela D’Angelo, Gloria Ros, Rossella Zanin, Michela Sgubin, Sara Petrosino, Sabrina Battista, and Guidalberto Manfioletti. "High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network." International Journal of Molecular Sciences 21, no. 3 (January 22, 2020): 717. http://dx.doi.org/10.3390/ijms21030717.

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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.

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Mao, Li, Kelsey J. Wertzler, Scott C. Maloney, Zeping Wang, Nancy S. Magnuson, and Raymond Reeves. "HMGA1 Levels Influence Mitochondrial Function and Mitochondrial DNA Repair Efficiency." Molecular and Cellular Biology 29, no. 20 (August 17, 2009): 5426–40. http://dx.doi.org/10.1128/mcb.00105-09.

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ABSTRACT HMGA chromatin proteins, a family of gene regulatory factors found at only low concentrations in normal cells, are almost universally overexpressed in cancer cells. HMGA proteins are located in the nuclei of normal cells except during the late S/G2 phases of the cell cycle, when HMGA1, one of the members of the family, reversibly migrates to the mitochondria, where it binds to mitochondrial DNA (mtDNA). In many cancer cells, this controlled shuttling is lost and HMGA1 is found in mitochondria throughout the cell cycle. To investigate the effects of HMGA1 on mitochondria, we employed a genetically engineered line of human MCF-7 cells in which the levels of transgenic HMGA1 protein could be reversibly controlled. “Turn-ON” and “turn-OFF” time course experiments were performed with these cells to either increase or decrease intracellular HMGA1 levels, and various mitochondrial changes were monitored. Results demonstrated that changes in both mtDNA levels and mitochondrial mass inversely paralleled changes in HMGA1 concentrations, strongly implicating HMGA1 in the regulation of these parameters. Additionally, the level of cellular reactive oxygen species (ROS) increased and the efficiency of repair of oxidatively damaged mtDNA decreased as consequences of elevated HMGA1 expression. Increased ROS levels and reduced repair efficiency in HMGA1-overexpressing cells likely contribute to the increased occurrence of mutations in mtDNA frequently observed in cancer cells.

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Minervini, Angela, Nicoletta Coccaro, Luisa Anelli, Antonella Zagaria, Giorgina Specchia, and Francesco Albano. "HMGA Proteins in Hematological Malignancies." Cancers 12, no. 6 (June 3, 2020): 1456. http://dx.doi.org/10.3390/cancers12061456.

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The high mobility group AT-Hook (HMGA) proteins are a family of nonhistone chromatin remodeling proteins known as “architectural transcriptional factors”. By binding the minor groove of AT-rich DNA sequences, they interact with the transcription apparatus, altering the chromatin modeling and regulating gene expression by either enhancing or suppressing the binding of the more usual transcriptional activators and repressors, although they do not themselves have any transcriptional activity. Their involvement in both benign and malignant neoplasias is well-known and supported by a large volume of studies. In this review, we focus on the role of the HMGA proteins in hematological malignancies, exploring the mechanisms through which they enhance neoplastic transformation and how this knowledge could be exploited to devise tailored therapeutic strategies.

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Vignali, Robert, Simone Macrì, Marco Onorati, Emanuela Basaldella, Riccardo Sgarra, and Guidalberto Manfioletti. "HMGA proteins in Xenopus laevis." Developmental Biology 319, no. 2 (July 2008): 589–90. http://dx.doi.org/10.1016/j.ydbio.2008.05.487.

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Reeves, Raymond. "HMGA proteins: flexibility finds a nuclear niche?" Biochemistry and Cell Biology 81, no. 3 (June 1, 2003): 185–95. http://dx.doi.org/10.1139/o03-044.

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The mammalian HMGA family of chromatin proteins possesses an unusual constellation of physical, biochemical, and biological characteristics that distinguish them from other nuclear proteins. Principal among these is the fact that, unlike other proteins, they possess little detectable secondary structure prior to interactions with other macromolecules (DNA, RNA, proteins). Upon binding to substrates, however, the HMGA proteins undergo specific disordered-to-ordered structural transitions and also induce alterations in the structure of the substrates themselves. Their intrinsic structural flexibility, combined with other features such as the control of their substrate interactions via complex patterns of in vivo biochemical modifications, allows the HMGA proteins to actively participate in a wide variety of nuclear activities including DNA replication, DNA repair, chromatin remodeling, control of gene transcription, and regulation of mRNA processing.Key words: chromatin, gene activation, high performance liquid chromatography, HMG-I(Y), mass spectrometry, transcription.

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Milcamps, Anne, Paolo Struffi, and Frans J. de Bruijn. "The Sinorhizobium melilotiNutrient-Deprivation-Induced Tyrosine Degradation GenehmgA Is Controlled by a Novel Member of thearsR Family of Regulatory Genes." Applied and Environmental Microbiology 67, no. 6 (June 1, 2001): 2641–48. http://dx.doi.org/10.1128/aem.67.6.2641-2648.2001.

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ABSTRACT The regulation of the nutrient-deprivation-inducedSinorhizobium meliloti homogentisate dioxygenase (hmgA) gene, involved in tyrosine degradation, was examined. hmgA expression was found to be independent of the canonical nitrogen regulation (ntr) system. To identify regulators of hmgA, secondary mutagenesis of anS. meliloti strain harboring a hmgA-luxABreporter gene fusion (N4) was carried out using transposon Tn1721. Two independent Tn1721 insertions were found to be located in a positive regulatory gene (nitR), encoding a protein sharing amino acid sequence similarity with proteins of the ArsR family of regulators. NitR was found to be a regulator of S. meliloti hmgA expression under nitrogen deprivation conditions, suggesting the presence of antr-independent nitrogen deprivation regulatory system.nitR insertion mutations were shown not to affect bacterial growth, nodulation of Medicago sativa(alfalfa) plants, or symbiotic nitrogen fixation under the physiological conditions examined. Further analysis of thenitR locus revealed the presence of open reading frames encoding proteins sharing amino acid sequence similarities with an ATP-binding phosphonate transport protein (PhnN), as well as transmembrane efflux proteins.

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Cayuela, María L., Montserrat Elías-Arnanz, Marcos Peñalver-Mellado, S. Padmanabhan, and Francisco J. Murillo. "The Stigmatella aurantiaca Homolog of Myxococcus xanthus High-Mobility-Group A-Type Transcription Factor CarD: Insights into the Functional Modules of CarD and Their Distribution in Bacteria." Journal of Bacteriology 185, no. 12 (June 15, 2003): 3527–37. http://dx.doi.org/10.1128/jb.185.12.3527-3537.2003.

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ABSTRACT Transcriptional factor CarD is the only reported prokaryotic analog of eukaryotic high-mobility-group A (HMGA) proteins, in that it has contiguous acidic and AT hook DNA-binding segments and multifunctional roles in Myxococcus xanthus carotenogenesis and fruiting body formation. HMGA proteins are small, randomly structured, nonhistone, nuclear architectural factors that remodel DNA and chromatin structure. Here we report on a second AT hook protein, CarDSa, that is very similar to CarD and that occurs in the bacterium Stigmatella aurantiaca. CarDSa has a C-terminal HMGA-like domain with three AT hooks and a highly acidic adjacent region with one predicted casein kinase II (CKII) phosphorylation site, compared to the four AT hooks and five CKII sites in CarD. Both proteins have a nearly identical 180-residue N-terminal segment that is absent in HMGA proteins. In vitro, CarDSa exhibits the specific minor-groove binding to appropriately spaced AT-rich DNA that is characteristic of CarD or HMGA proteins, and it is also phosphorylated by CKII. In vivo, CarDSa or a variant without the single CKII phosphorylation site can replace CarD in M. xanthus carotenogenesis and fruiting body formation. These two cellular processes absolutely require that the highly conserved N-terminal domain be present. Thus, three AT hooks are sufficient, the N-terminal domain is essential, and phosphorylation in the acidic region by a CKII-type kinase can be dispensed with for CarD function in M. xanthus carotenogenesis and fruiting body development. Whereas a number of hypothetical proteins homologous to the N-terminal region occur in a diverse array of bacterial species, eukaryotic HMGA-type domains appear to be confined primarily to myxobacteria.

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Giancotti, Vincenzo, Natascha Bergamin, Palmina Cataldi, and Claudio Rizzi. "Epigenetic Contribution of High-Mobility Group A Proteins to Stem Cell Properties." International Journal of Cell Biology 2018 (2018): 1–20. http://dx.doi.org/10.1155/2018/3698078.

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High-mobility group A (HMGA) proteins have been examined to understand their participation as structural epigenetic chromatin factors that confer stem-like properties to embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and cancer stem cells (CSCs). The function of HMGA was evaluated in conjunction with that of other epigenetic factors such as histones and microRNAs (miRs), taking into consideration the posttranscriptional modifications (PTMs) of histones (acetylation and methylation) and DNA methylation. HMGA proteins were coordinated or associated with histone and DNA modification and the expression of the factors related to pluripotency. CSCs showed remarkable differences compared with ESCs and iPSCs.

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Fusco, Alfredo, and Monica Fedele. "Roles of HMGA proteins in cancer." Nature Reviews Cancer 7, no. 12 (December 2007): 899–910. http://dx.doi.org/10.1038/nrc2271.

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De Martino, Ivana, Rosa Visone, Dario Palmieri, Paolo Cappabianca, Paolo Chieffi, Floriana Forzati, Antonio Barbieri, et al. "The Mia/Cd-rap gene expression is downregulated by the high-mobility group A proteins in mouse pituitary adenomas." Endocrine-Related Cancer 14, no. 3 (September 2007): 875–86. http://dx.doi.org/10.1677/erc-07-0036.

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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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Grasser, Klaus D. "Chromatin-associated HMGA and HMGB proteins: versatile co-regulators of DNA-dependent processes." Plant Molecular Biology 53, no. 3 (October 2003): 281–95. http://dx.doi.org/10.1023/b:plan.0000007002.99408.ba.

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Ziółkowski, Piotr, Elżbieta Gamian, Beata Osiecka, Alexandre Zougman, and Jacek R. Wiśniewski. "Immunohistochemical and Proteomic Evaluation of Nuclear Ubiquitous Casein and Cyclin-Dependent Kinases Substrate in Invasive Ductal Carcinoma of the Breast." Journal of Biomedicine and Biotechnology 2009 (2009): 1–8. http://dx.doi.org/10.1155/2009/919645.

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Nuclear ubiquitous casein and cyclin-dependent kinases substrate (NUCKS) is 27 kDa chromosomal protein of unknown function. Its amino acid composition as well as structure of its DNA binding domain resembles that of high-mobility group A, HMGA proteins. HMGA proteins are associated with various malignancies. Since changes in expression of HMGA are considered as marker of tumor progression, it is possible that similar changes in expression of NUCKS could be useful tool in diagnosis and prognosis of breast cancer. For identification and analysis of NUCKS we used proteomic and histochemical methods. Analysis of patient-matched samples of normal and breast cancer by mass spectrometry revealed elevated levels of NUCKS in protein extracts from ductal breast cancers. We elicited specific antibodies against NUCKS and used them for immunohistochemistry in invasive ductal carcinoma of breast. We found high expression of NUCKS in 84.3% of cancer cells. We suggest that such overexpression of NUCKS can play significant role in breast cancer biology.

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Lichota, Jacek, and Klaus D. Grasser. "Differential Chromatin Association and Nucleosome Binding of the Maize HMGA, HMGB, and SSRP1 Proteins†." Biochemistry 40, no. 26 (July 2001): 7860–67. http://dx.doi.org/10.1021/bi010548y.

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Grasser, Klaus D., Winfried Hetz, and G�nter Feix. "Stability of the maize chromosomal high-mobility-group proteins, HMGa and HMGb,in vivo." Plant Molecular Biology 25, no. 3 (June 1994): 565–68. http://dx.doi.org/10.1007/bf00043885.

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Fedele, Monica, and Alfredo Fusco. "Role of the high mobility group A proteins in the regulation of pituitary cell cycle." Journal of Molecular Endocrinology 44, no. 6 (March 10, 2010): 309–18. http://dx.doi.org/10.1677/jme-09-0178.

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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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Peluso, Silvia, and Gennaro Chiappetta. "High-Mobility Group A (HMGA) Proteins and Breast Cancer." Breast Care 5, no. 2 (2010): 81–85. http://dx.doi.org/10.1159/000297717.

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Reeves, Raymond. "Molecular biology of HMGA proteins: hubs of nuclear function." Gene 277, no. 1-2 (October 2001): 63–81. http://dx.doi.org/10.1016/s0378-1119(01)00689-8.

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D’Angelo, Daniela, Paula Mussnich, Claudio Arra, Sabrina Battista, and Alfredo Fusco. "Critical role of HMGA proteins in cancer cell chemoresistance." Journal of Molecular Medicine 95, no. 4 (March 14, 2017): 353–60. http://dx.doi.org/10.1007/s00109-017-1520-x.

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Moliterno, Alison R., Donna Marie Williams, Liping Li, Lingling Xian, Li Luo, Amy S. Duffield, Ophelia Rogers, Jerry L. Spivak, and Linda Resar. "The High Mobility Group A1 Chromatin Regulator Is Required for Pathologic Megakaryocyte Development and Progression to Myelofibrosis in JAK2V617F Murine Models." Blood 134, Supplement_1 (November 13, 2019): 472. http://dx.doi.org/10.1182/blood-2019-131432.

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Introduction: JAK2V617F-positive myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by unregulated JAK2/STAT signaling and increased risk of transformation to myelofibrosis (MF). Pathologic JAK2/STAT signaling of the thrombopoietin/thrombopoietin receptor pathway in HSC, progenitors, and megakaryocytes drives megakaryocytic proliferation, megakaryocytic hypertrophy, thrombocytosis, HSC niche damage, osteosclerosis, myelofibrosis, and extramedullary hematopoiesis (EMH). The High Mobility Group A1/2 (HMGA1/2) genes encode oncogenic chromatin remodeling proteins that foster aberrant STAT3 signaling in diverse contexts. In murine models, Hmga1/2 overexpression drives clonal expansion and deregulated proliferation. In patients with MPN, HMGA1/2 genes are overexpressed with disease progression to MF. We therefore sought to: 1) elucidate mechanisms mediated by HMGA1/2 in JAK2V617F-associated MF transformation and 2) test the hypothesis that HMGA proteins are rational therapeutic targets for MF progression. Methods: We used a JAK2V617F transgenic murine model (VF) in which 13 copies of the human JAK2V617F cDNA are driven by the Vav promoter (Blood 2008; 111:5109-5117). To elucidate the function of Hmga1 or Hmga2 in the JAK2V617F context, we crossed VF mice onto a background deficient for Hmga1 or Hmga2 to generate VF/Hmga1+/- and VF/Hmga2+/- progeny. We also generated a tissue specific model whereby Hmga1 was deleted in HSC via Vav-cre (Vav-cre Hmga1+/-) and crossed these mice onto the VF model (VF/Vav-cre Hmga1+/-). Serial blood counts, histology of marrow and spleen, and immunohistochemistry with CD61 antibodies were compared in each model at 8, 16, and/or 40 weeks of age. We also performed flow cytometric analysis of HSC and progenitor populations in mice with these genotypes. Results: The VF mice develop an MPN phenotype by 8 weeks with marked thrombocytosis and erythrocytosis. By 33 weeks, VF mice progress to MF characterized by anemia, splenomegaly due to extramedullary hematopoiesis (EMH), marked megakaryocytic hyperplasia, megakaryocytic hypertrophy, increased platelet size, and osteosclerosis with reticulin fibrosis (Figure A and B). ). The VF mouse also develops an expansion of megakaryocyte-erythroid progenitors (MEP) compared to wildtype mice (P<0.01). Neither mice with Hmga1deficiency (Hmga1+/- or Hmga1-/-) nor Hmga2+/- mice develop thrombocytopenia or other blood count abnormalities at one year of age, and preliminary data suggests that the MEP compartment is normal in Hmga1+/- and Hmga1-/- mice. However, VF/Hmga1+/- mice had reduction of both megakaryocyte hypertrophy and hyperplasia, bone marrow fibrosis, and osteosclerosis compared to VF mice at corresponding age ranges (Figure A). Further, there was mitigation of thrombocytosis, reduction in platelet size, and decreased spleen weight in VF/Hmga1+/- mice compared to VF mice at corresponding age ranges (Figure B). Importantly, VF/Hmga1+/- mice fail to develop anemia which occurs after 33 weeks in the VF model (VF hemoglobin 12.9 g/dl, VF/Hmga1+/- hemoglobin 15.1 g/dl, P<.05). In VF/Hmga1-/- mice, there was no expansion in MEP. The MPN progression to MF was prevented by both global or HSC-specific heterozygous Hmga1 deficiency, demonstrating that the effects of Hmga1 are specific to the hematopoietic cell context rather than the bone marrow microenvironment. In addition, similar degrees of mitigation were observed in VF mice with heterozygous or homozygous Hmga1 deficiency. In contrast, Hmga2 deficiency failed to prevent progression in the VF model. Unexpectedly, Hmga2 deficiency exacerbated megakaryocyte hypertrophy and reticulin fibrosis in VF mice. Conclusions: In a JAK2V617F murine model, heterozygous deficiency of Hmga1 prevents MPN progression to MF, interrupting both the development of megakaryocytic hyperplasia and fibrosis, which are hallmarks of murine and human JAK2V617F disease. While Hmga1 is not required for megakaryocyte or platelet development under steady state conditions, it is critical to the amplification of aberrant signaling in MF associated VF. Further, our findings underscore a key role for HMGA1 as a mediator of aberrant JAK2/STAT3 signaling and a therapeutic target to quell myeloproliferation and prevent MF progression. Disclosures Duffield: Boston Biomedical/Sumitomo Dainippon Pharma Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; MedImmune: Consultancy.

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Resar, Linda, Donna Marie Williams, Lingling Xian, Wenyan Lu, Briyana Chisholm, Li Luo, Zhizhuang Joe Zhao, Ophelia Rogers, Jerry L. Spivak, and Alison R. Moliterno. "High Mobility Group A1 Chromatin Remodeling Proteins Amplify Inflammatory Networks to Drive Leukemic Transformation in Chronic Myeloproliferative Neoplasia in Humans and JAK2V617F Transgenic Mouse Models." Blood 132, Supplement 1 (November 29, 2018): 102. http://dx.doi.org/10.1182/blood-2018-99-119549.

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Abstract Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by overproduction of mature blood cells and increased risk of transformation to myelofibrosis (MF) and acute myeloid leukemia (AML), although molecular mechanisms driving disease progression remain elusive. While most patients who acquire a JAK2V617F mutation in CD34+ cells present with chronic, indolent Polycythemia Vera (PV), ~25% will progress to MF or AML. High Mobility Group A1/2 (HMGA1/2) genes encode oncogenic chromatin remodeling proteins which are overexpressed in aggressive leukemia where they portend adverse outcomes. In murine models, Hmga1/2 overexpression drives clonal expansion and uncontrolled proliferation. HMGA1/2 genes are also overexpressed in MPN with disease progression. We therefore sought to: 1) test the hypothesis that HMGA proteins are required for leukemic transformation and rational therapeutic targets in MPN progression, and, 2) identify mechanisms mediated by HMGA1/2 during disease progression. Methods: We measured HMGA1/2 in JAK2V617F mutant human AML cell lines from MPN patients (DAMI, SET-2), CD34+ cells from PV patients during chronic and transformation phases, and JAK2V617F transgenic murine models of PV (transgenic JAK2V617F) and PV-AML (transgenic JAK2V617F/MPLSV; Blood 2015;126:484). To elucidate HMGA1/2 function, we silenced HMGA1 or HMGA2 via short hairpin RNA in human MPN-AML cell lines (DAMI, SET-2) and assessed proliferation, colony formation, and leukemic engraftment in immunodeficient mice. To further assess Hmga1 function in vivo, we crossed mice with heterozygous Hmga1 deficiency onto murine models of PV and PV-AML. Finally, to dissect molecular mechanisms underlying HMGA1, we compared RNA-Seq from MPN-AML cell lines (DAMI, SET-2) after silencing HMGA1/2 to that of controls and applied Ingenuity Pathway Analysis. Results: HMGA1/2 mRNA are up-regulated in all JAK2V617F-positive contexts, including primary human PV CD34+ cells and total bone marrow from JAK2V617F mouse models for PV compared to controls. Further, there is a marked up-regulation in both HMGA1/2 in CD34+ cells from PV patients after transformation to MF or AML and in leukemic blasts from our PV-AML mouse model compared to PV mice. Overexpression of HMGA1/2 also correlates with clonal dominance of human JAK2V617F-homozygous stem cells and additional mutations of epigenetic regulators (EZH2, SETBP1). Silencing HMGA1 or HMGA2 in human MPN-AML cell lines (DAMI, SET-2) dramatically halts proliferation, disrupts clonogenicity, and prevents leukemic engraftment in mice. Further, heterozygous Hmga1 deficiency decreases splenic enlargement in PV mouse models with advancing age. Moreover, heterozygous Hmga1 deficiency prolongs survival in the transgenic PV-AML murine model with fulminant leukemia and early mortality. PV-AML mice survived a median of 5 weeks whereas PV-AML mice with heterozygous Hmga1 deficiency survive a median of 12 weeks (P< 0.002). The leukemic burden was also decreased in mice with Hmga1 deficiency. Preliminary RNA-Seq analyses from DAMI and SET-2 cells show that HMGA1 drives pathways involved in Th1/Th2 activation, chemotaxis, cell-cell signaling, myeloid cell accumulation and other immune cell trafficking, inflammation, and injury, suggesting that HMGA1 co-opts immune and inflammatory networks to drive tumor progression. Surprisingly, atherosclerosis pathways are also induced by HMGA1. Conclusions: HMGA1/2 genes are overexpressed in MPN with highest levels in more advanced disease (MF, AML) both in primary human tumors and murine models. Strikingly, silencing HMGA1 or HMGA2 halts proliferation and clonogenicity in vitro and prevents leukemic engraftment in vivo. Further, heterozygous Hmga1 deficiency prolongs survival in a murine model of fulminant MPN AML and decreases tumor burdens. Finally, preliminary RNA-Seq analyses suggest that HMGA1 amplifies transcriptional networks involved in immune cell trafficking and inflammation to drive tumor progression. Unexpectedly, HMGA1 also regulates pathways involved in atherosclerosis, implicating HMGA1 as a novel link between clonal hematopoiesis and cardiovascular disease. Our findings further highlight HMGA1/2 as a key molecular switch for leukemic transformation in MPN and opens the door to novel therapeutic approaches to prevent disease progression. Disclosures No relevant conflicts of interest to declare.

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V, Giancotti, Cataldi P, and Rizzi C. "Roles of HMGA proteins in cancer: Expression, pathways, and redundancies." Journal of Modern Human Pathology 1, no. 6 (October 7, 2016): 44–62. http://dx.doi.org/10.14312/2397-6845.2016-8.

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Helmke, B. M., D. N. Markowski, M. H. Muller, A. Sommer, J. Muller, C. Moller, and J. Bullerdiek. "HMGA proteins regulate the expression of FGF2 in uterine fibroids." Molecular Human Reproduction 17, no. 2 (October 6, 2010): 135–42. http://dx.doi.org/10.1093/molehr/gaq083.

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De Martino, Ivana, Rosa Visone, Anne Wierinckx, Dario Palmieri, Angelo Ferraro, Paolo Cappabianca, Gennaro Chiappetta, et al. "HMGA Proteins Up-regulate CCNB2 Gene in Mouse and Human Pituitary Adenomas." Cancer Research 69, no. 5 (February 17, 2009): 1844–50. http://dx.doi.org/10.1158/0008-5472.can-08-4133.

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Saperas, N., R. Sánchez-Giraldo, E. Fonfría-Subirós, G. Sanahuja, M. Pagán, S. Rodríguez-Puente, and J. L. Campos. "HMGA proteins as therapeutic drug targets: interaction of DNA with human HMGA1a." New Biotechnology 25 (September 2009): S6. http://dx.doi.org/10.1016/j.nbt.2009.06.016.

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Palmieri, D., T. Valentino, D. D'Angelo, I. De Martino, I. Postiglione, R. Pacelli, C. M. Croce, M. Fedele, and A. Fusco. "HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents." Oncogene 30, no. 27 (February 21, 2011): 3024–35. http://dx.doi.org/10.1038/onc.2011.21.

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De Martino, Ivana, Rosa Visone, Anne Wierinckx, Dario Palmieri, Angelo Ferraro, Paolo Cappabianca, Gennaro Chiappetta, et al. "Retraction: HMGA Proteins Up-regulate CCNB2 Gene in Mouse and Human Pituitary Adenomas." Cancer Research 78, no. 24 (December 13, 2018): 6906. http://dx.doi.org/10.1158/0008-5472.can-18-3455.

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Lyngaard, Carina, Christian Stemmer, Allan Stensballe, Manuela Graf, Gilbert Gorr, Eva Decker, and Klaus D. Grasser. "Physcomitrella HMGA-type proteins display structural differences compared to their higher plant counterparts." Biochemical and Biophysical Research Communications 374, no. 4 (October 2008): 653–57. http://dx.doi.org/10.1016/j.bbrc.2008.07.091.

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Hui, Pei, Ning Li, Chaline Johnson, Ivo De Wever, Raf Sciot, Guidalberto Manfioletti, and Giovanni Tallini. "HMGA proteins in malignant peripheral nerve sheath tumor and synovial sarcoma: preferential expression of HMGA2 in malignant peripheral nerve sheath tumor." Modern Pathology 18, no. 11 (July 29, 2005): 1519–26. http://dx.doi.org/10.1038/modpathol.3800464.

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Sgarra, Riccardo, Silvia Pegoraro, Gloria Ros, Carlotta Penzo, Eusebio Chiefari, Daniela Foti, Antonio Brunetti, and Guidalberto Manfioletti. "High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression." Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1869, no. 2 (April 2018): 216–29. http://dx.doi.org/10.1016/j.bbcan.2018.03.001.

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Zhao, Bo, Yanpeng Xi, Junghyun Kim, and Sibum Sung. "Chromatin architectural proteins regulate flowering time by precluding gene looping." Science Advances 7, no. 24 (June 2021): eabg3097. http://dx.doi.org/10.1126/sciadv.abg3097.

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Chromatin structure is critical for gene expression and many other cellular processes. In Arabidopsis thaliana, the floral repressor FLC adopts a self-loop chromatin structure via bridging of its flanking regions. This local gene loop is necessary for active FLC expression. However, the molecular mechanism underlying the formation of this class of gene loops is unknown. Here, we report the characterization of a group of linker histone-like proteins, named the GH1-HMGA family in Arabidopsis, which act as chromatin architecture modulators. We demonstrate that these family members redundantly promote the floral transition through the repression of FLC. A genome-wide study revealed that this family preferentially binds to the 5′ and 3′ ends of gene bodies. The loss of this binding increases FLC expression by stabilizing the FLC 5′ to 3′ gene looping. Our study provides mechanistic insights into how a family of evolutionarily conserved proteins regulates the formation of local gene loops.

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Pierre-Louis, Olivier, Joris Andrieux, Christophe Desterke, Eric Lippert, Vincent Praloran, Jean-Loup Demory, Marie-Caroline Le Bousse-Kerdiles, and Chrystele Bilhou-Nabera. "Discriminative HMGA2 Isoform Expression in CD15+ Granulocytic Cells in Myeloid Metaplasia with Myelofibrosis (MMM)." Blood 104, no. 11 (November 16, 2004): 2429. http://dx.doi.org/10.1182/blood.v104.11.2429.2429.

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Abstract MMM is a myeloproliferative disorder characterized by extramedullary hematopoiesis and reactive myelofibrosis. Recently, HMGA2 dysregulation has been demonstrated in 2 MMM patients showing 12q15 rearrangement and confirmed in 25 consecutive MMM patients without cytogenetic abnormalities (Andrieux, 2004). HMGA2 proteins belong to the high mobility group A (HMGA) family of architectural transcription factors regulating the expression of several genes. As MMM is a clonal disorder of CD34+ hematopoietic progenitors, we analyzed HMGA2 expression in peripheral blood sub-populations of 5 MMM patients and 7 healthy donors to determine in which sub-population HMGA2 was dysregulated. RNA was extracted from peripheral blood mononuclear cells (PBMC) and CD15+ granulocytic cells (PBCD15+) separated through Ficoll centrifugation or from immunomagnetically selected circulating CD34+ cells (PBCD34+). Real-time quantitative PCR (RQ-PCR) using Taqman technology was performed on cDNA. As different isoforms were described in malignancies, we used two primer sets : the first one allowing the amplification of all HMGA2 isoforms (exon 1 to 3) (HMGA2 1–3), the second one allowing the amplification of the full length HMGA2 isoform (exon 1 to 5)(HMGA2 1–5). In healthy donors and in MMM, PBMC HMGA2 expression levels were heterogeneous, depending of the cellular sub-population purity. HMGA2 1–3 or HMGA2 1–5 were both expressed in MMM and normal PBCD34+ cells, but with a higher expression level for HMGA2 1–3 as compared to HMGA2 1–5. Furthermore, both HMGA2 1–3 and HMGA2 1–5 expression levels were significantly increased in PBCD34+ MMM patients (p<10−6) compared to healthy donors. In MMM, HMGA2 expression level was significantly increased (p<10−5) in PBCD15+ as compared to PBCD34+. Moreover, PBCD15+ HMGA2 1–3 expression level was significantly higher in MMM patients compared to PBCD15+ from healthy donors (p<10−7). A persistence of HMGA2 1–5 expression was only observed in MMM PBCD15+ but was undetectable neither in normal PB neutrophils (purity>98%) nor in PB neutrophils from other myeloproliferative disorders (Polycythemia Vera and Essential Thrombocythemia). To determine if HMGA2 level was modified during hematopoietic differentiation, we quantified HMGA2 1–3 and 1–5 isoform expression on purified healthy donor PB CD34+ and MMM CD34+ before and after culture with specific lineage growth factors (12 day-culture). Primary results showed that both HMGA2 isoform expression levels were higher during granulocytic differentiation. Our results demonstrate that HMGA2 1–5 isoform is discriminately overexpressed in MMM PBCD15+. The persistence of this HMGA2 full length expression in MMM myeloid lineage could be considered as a marker of the disease.

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LeRoy, Gary, Ozgur Oksuz, Nicolas Descostes, Yuki Aoi, Rais A. Ganai, Havva Ortabozkoyun Kara, Jia-Ray Yu, et al. "LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription in differentiated cells." Science Advances 5, no. 10 (October 2019): eaay3068. http://dx.doi.org/10.1126/sciadv.aay3068.

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FACT (facilitates chromatin transcription) is a protein complex that allows RNA polymerase II (RNAPII) to overcome the nucleosome-induced barrier to transcription. While abundant in undifferentiated cells and many cancers, FACT is not abundant or is absent in most tissues. Therefore, we screened for additional proteins that might replace FACT upon differentiation. We identified two proteins, lens epithelium-derived growth factor (LEDGF) and hepatoma-derived growth factor 2 (HDGF2), each containing two high mobility group A (HMGA)–like AT-hooks and a methyl-lysine reading Pro-Trp-Trp-Pro (PWWP) domain that binds to H3K36me2 and H3K36me3.LEDGF and HDGF2 colocalize with H3K36me2/3 at genomic regions containing active genes. In myoblasts, LEDGF and HDGF2 are enriched on most active genes. Upon differentiation to myotubes, LEDGF levels decrease, while HDGF2 levels are maintained. Moreover, HDGF2 is required for their proper expression. HDGF2 knockout myoblasts exhibit an accumulation of paused RNAPII within the transcribed region of many HDGF2 target genes, indicating a defect in early elongation.

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Zhang, Rugang, Wei Chen, and Peter D. Adams. "Molecular Dissection of Formation of Senescence-Associated Heterochromatin Foci." Molecular and Cellular Biology 27, no. 6 (January 22, 2007): 2343–58. http://dx.doi.org/10.1128/mcb.02019-06.

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ABSTRACTSenescence is characterized by an irreversible cell proliferation arrest. Specialized domains of facultative heterochromatin, calledsenescence-associatedheterochromatinfoci (SAHF), are thought to contribute to the irreversible cell cycle exit in many senescent cells by repressing the expression of proliferation-promoting genes such as cyclin A. SAHF contain known heterochromatin-forming proteins, such asheterochromatinprotein1(HP1) and the histone H2A variant macroH2A, and other specialized chromatin proteins, such as HMGA proteins. Previously, we showed that a complex of histone chaperones,histonerepressorA(HIRA) andantisilencingfunction1a(ASF1a), plays a key role in the formation of SAHF. Here we have further dissected the series of events that contribute to SAHF formation. We show that each chromosome condenses into a single SAHF focus. Chromosome condensation depends on the ability of ASF1a to physically interact with its deposition substrate, histone H3, in addition to its cochaperone, HIRA. In cells entering senescence, HP1γ, but not the related proteins HP1α and HP1β, becomes phosphorylated on serine 93. This phosphorylation is required for efficient incorporation of HP1γ into SAHF. Remarkably, however, a dramatic reduction in the amount of chromatin-bound HP1 proteins does not detectably affect chromosome condensation into SAHF. Moreover, abundant HP1 proteins are not required for the accumulation in SAHF of histone H3 methylated on lysine 9, the recruitment of macroH2A proteins, nor other hallmarks of senescence, such as the expression of senescence-associated β-galactosidase activity and senescence-associated cell cycle exit. Based on our results, we propose a stepwise model for the formation of SAHF.

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García-Heras, Francisco, Javier Abellón-Ruiz, Francisco J. Murillo, S. Padmanabhan, and Montserrat Elías-Arnanz. "High-Mobility-Group A-Like CarD Binds to a DNA Site Optimized for Affinity and Position and to RNA Polymerase To Regulate a Light-Inducible Promoter in Myxococcus xanthus." Journal of Bacteriology 195, no. 2 (November 9, 2012): 378–88. http://dx.doi.org/10.1128/jb.01766-12.

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ABSTRACTThe CarD-CarG complex controls various cellular processes in the bacteriumMyxococcus xanthusincluding fruiting body development and light-induced carotenogenesis. The CarD N-terminal domain, which defines the large CarD_CdnL_TRCF protein family, binds to CarG, a zinc-associated protein that does not bind DNA. The CarD C-terminal domain resembles eukaryotic high-mobility-group A (HMGA) proteins, and its DNA binding AT hooks specifically recognize the minor groove of appropriately spaced AT-rich tracts. Here, we investigate the determinants of the only known CarD binding site, the one crucial in CarD-CarG regulation of the promoter of thecarQRSoperon (PQRS), a light-inducible promoter dependent on the extracytoplasmic function (ECF) σ factor CarQ.In vitro, mutating either of the 3-bp AT tracts of this CarD recognition site (TTTCCAGAGCTTT) impaired DNA binding, shifting the AT tracts relative to PQRShad no effect or marginally lowered DNA binding, and replacing the native site by the HMGA1a binding one at the human beta interferon promoter (with longer AT tracts) markedly enhanced DNA binding.In vivo, however, all of these changes deterred PQRSactivation in wild-typeM. xanthus, as well as in a strain with the CarD-CarG pair replaced by theAnaeromyxobacter dehalogenansCarD-CarG (CarDAd-CarGAd). CarDAd-CarGAdis functionally equivalent to CarD-CarG despite the lower DNA binding affinityin vitroof CarDAd, whose C-terminal domain resembles histone H1 rather than HMGA. We show that CarD physically associates with RNA polymerase (RNAP) specifically via interactions with the RNAP β subunit. Our findings suggest that CarD regulates a light-inducible, ECF σ-dependent promoter by coupling RNAP recruitment and binding to a specific DNA site optimized for affinity and position.

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Pal Negi, Archana, Ratnesh Singh, Anupma Sharma, and Vishal Singh Negi. "Insights into high mobility group A (HMGA) proteins from Poaceae family: An in silico approach for studying homologs." Computational Biology and Chemistry 87 (August 2020): 107306. http://dx.doi.org/10.1016/j.compbiolchem.2020.107306.

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Sobajima, J., S. Ozaki, H. Uesugi, F. Osakada, M. Inoue, Y. Fukuda, H. Shirakawa, et al. "High mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 are significant target antigens of perinuclear anti-neutrophil cytoplasmic antibodies in autoimmune hepatitis." Gut 44, no. 6 (June 1, 1999): 867–73. http://dx.doi.org/10.1136/gut.44.6.867.

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Abstract:

BACKGROUNDHigh mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 have been identified as novel antigens of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCAs), and the existence of anti-HMG1 and anti-HMG2 antibodies in a population of patients with ulcerative colitis has been reported.AIMSTo investigate whether HMG1 and HMG2 are target antigens for p-ANCAs in autoimmune hepatitis (AIH).PATIENTSSerum samples from 28 patients with AIH, 44 patients with primary biliary cirrhosis (PBC), 27 patients with chronic hepatitis C, and 23 patients with chronic hepatitis B were tested.METHODSANCAs were detected by routine indirect immunofluorescence (IIF). Anti-HMG1 and anti-HMG2 antibodies were assayed by enzyme linked immunosorbent assay.RESULTSp-ANCAs were detected in 89% (25/28) of patients with AIH, 36% (16/44) of patients with PBC, 11% (3/27) of patients with chronic hepatitis C, and 13% (3/23) of patients with chronic hepatitis B. Anti-HMG1 and/or anti-HMG2 antibodies were detected in 89% (25/28) of patients with AIH, 70% (31/44) with PBC, 26% (7/27) with chronic hepatitis C, and 9% (2/23) with chronic hepatitis B. In AIH, anti-HMG1 and/or anti-HMG2 antibodies were detected in 96% (24/25) of p-ANCA positive patients. The p-ANCA staining pattern detected by IIF using sera from patients with AIH disappeared or decreased in titre after preincubation with a mixture of HMG1/HMG2. The presence and titres of those antibodies in AIH correlated significantly with those of p-ANCA, but not with those of anti-nuclear antibody or anti-smooth muscle antibody.CONCLUSIONSHMG1 and HMG2 are significant target antigens of p-ANCA in AIH.

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D’Angelo, Daniela, Paula Mussnich, Romina Sepe, Maddalena Raia, Luigi del Vecchio, Paolo Cappabianca, Simona Pellecchia, et al. "RPSAP52 lncRNA is overexpressed in pituitary tumors and promotes cell proliferation by acting as miRNA sponge for HMGA proteins." Journal of Molecular Medicine 97, no. 7 (May 10, 2019): 1019–32. http://dx.doi.org/10.1007/s00109-019-01789-7.

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Journal articles on the topic 'HMGA proteins'

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