The Experts below are selected from a list of 6084 Experts worldwide ranked by ideXlab platform
Alfredo Fusco - One of the best experts on this subject based on the ideXlab platform.
-
Epigenetic Mechanisms Leading to Overexpression of HMGA Proteins in Human Pituitary Adenomas
Frontiers in medicine, 2015Co-Authors: D D'angelo, Francesco Esposito, Alfredo FuscoAbstract:Overexpression of the HMGA1 and HMGA2 proteins is a feature of all human pituitary adenoma subtypes. However, amplification and/or rearrangement of the HMGA2 have been described in human prolactinomas, but rarely in other pituitary subtypes, and no genomic amplification of HMGA1 was detected in pituitary adenomas. Here, we summarize the functional role of HMGA proteins in pituitary tumorigenesis and the epigenetic mechanisms contributing to HMGA overexpression in these tumors focusing on recent studies indicating a critical role of non coding RNAs in modulating HMGA protein levels.
-
HMGA1 pseudogene expression is induced in human pituitary tumors
Cell Cycle, 2015Co-Authors: Francesco Esposito, Marco De Martino, Daniela Dangelo, Paula Mussnich, M L Jaffrainrea, J. Trouillas, Filippo Fraggetta, Gerald Raverot, Alfredo FuscoAbstract:Numerous studies have established that High Mobility Group A (HMGA) proteins play a pivotal role on the onset of human pituitary tumors. They are overexpressed in pituitary tumors, and, consistently, transgenic mice overexpressing either the HMGA1 or the HMGA2 gene develop pituitary tumors. In contrast with HMGA2, HMGA1 overexpression is not related to any rearrangement or amplification of the HMGA1 locus in these tumors. We have recently identified 2 HMGA1 pseudogenes, HMGA1P6 and HMGA1P7, acting as competitive endogenous RNA decoys for HMGA1 and other cancer related genes. Here, we show that HMGA1 pseudogene expression significantly correlates with HMGA1 mRNA levels in growth hormone and nonfunctioning pituitary adenomas likely inhibiting the repression of HMGA1 through microRNAs action. According to our functional studies, these HMGA1 pseudogenes enhance the proliferation and migration of the mouse pituitary tumor cell line, at least in part, through their upregulation. Our results point out that the o...
-
High mobility group a proteins as tumor markers
Frontiers in medicine, 2015Co-Authors: Pierlorenzo Pallante, Romina Sepe, Francesca Puca, Alfredo FuscoAbstract:Almost 30 years ago, overexpression of HMGA proteins was associated with malignant phenotype of rat thyroid cells transformed with murine retroviruses. Thereafter, several studies have analyzed HMGA expression in a wide range of human neoplasias. Here, we summarize all these results that, in the large majority of the cases, confirm the association of HMGA overexpression with high malignant phenotype as outlined by chemoresistance, spreading of metastases, and a global poor survival. Even though HMGA proteins’ overexpression indicates a poor prognosis in almost all malignancies, their detection may be particularly useful in determining the prognosis of breast, lung, and colon carcinomas, suggesting for the treatment a more aggressive therapy. In particular, the expression of HMGA2 in lung carcinomas is frequently associated with the presence of metastases. Moreover, recent data revealed that often the cause for the high HMGA proteins levels detected in human malignancies is a deregulated expression of non-coding RNA. Therefore, the HMGA proteins represent tumor markers whose detection can be a valid tool for the diagnosis and prognosis of neoplastic diseases.
-
HMGA1 pseudogenes as candidate proto oncogenic competitive endogenous rnas
Oncotarget, 2014Co-Authors: Francesco Esposito, Marco De Martino, Floriana Forzati, Giovanna Maria Pierantoni, Maria Grazia Petti, Mara Tornincasa, Antonella Federico, Claudio Arra, Alfredo FuscoAbstract:The High Mobility Group A (HMGA) are nuclear proteins that participate in the organization of nucleoprotein complexes involved in chromatin structure, replication and gene transcription. HMGA overexpression is a feature of human cancer and plays a causal role in cell transformation. Since non-coding RNAs and pseudogenes are now recognized to be important in physiology and disease, we investigated HMGA1 pseudogenes in cancer settings using bioinformatics analysis. Here we report the identification and characterization of two HMGA1 non-coding pseudogenes, HMGA1P6 and HMGA1P7. We show that their overexpression increases the levels of HMGA1 and other cancer-related proteins by inhibiting the suppression of their synthesis mediated by microRNAs. Consistently, embryonic fibroblasts from HMGA1P7-overexpressing transgenic mice displayed a higher growth rate and reduced susceptibility to senescence. Moreover, HMGA1P6 and HMGA1P7 were overexpressed in human anaplastic thyroid carcinomas, which are highly aggressive, but not in differentiated papillary carcinomas, which are less aggressive. Lastly, the expression of the HMGA1 pseudogenes was significantly correlated with HMGA1 protein levels thereby implicating HMGA1P overexpression in cancer progression. In conclusion, HMGA1P6 and HMGA1P7 are potential proto-oncogenic competitive endogenous RNAs.
-
Pituitary Adenoma: Role of HMGA Proteins
Tumors of the Central Nervous System Volume 10, 2012Co-Authors: Monica Fedele, Alfredo FuscoAbstract:Pituitary tumors are in most cases monoclonal adenomas arising from the adenohypophysial cells, and represent about 15% of intracranial tumors. They, while benign tumors, show a significant morbidity related to the endocrinological symptoms of hypo-or hyper-secretion of hormones and/or mass effect of the tumor on adjacent brain structures. Despite their considerable social impact, yet relatively little is known about the molecular events underlying pituitary tumorigenesis. Recent studies have demonstrated that the High Mobility Group A (HMGA) gene family, including HMGA1 and HMGA2, has a critical role in the development of pituitary adenomas. Indeed, the HMGA2 gene is amplified and overexpressed in several pituitary adenomas, and, consistently, transgenic mice overexpressing either HMGA1 or HMGA2 develop pituitary adenomas. The overxpression of the HMGA proteins would induce pituitary adenomas mainly by enhancing the activity of the transcription factor E2F1 and by upregulating the expression of cyclin B2 and other genes involved in the regulation of the cell cycle.
Guidalberto Manfioletti - One of the best experts on this subject based on the ideXlab platform.
-
High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network.
International journal of molecular sciences, 2020Co-Authors: Riccardo Sgarra, D D'angelo, Silvia Pegoraro, Sara Petrosino, Gloria Ros, Rossella Zanin, Michela Sgubin, Sabrina Battista, Guidalberto ManfiolettiAbstract: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.
-
High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression.
Biochimica et biophysica acta. Reviews on cancer, 2018Co-Authors: Riccardo Sgarra, Eusebio Chiefari, Silvia Pegoraro, Antonio Brunetti, Gloria Ros, Carlotta Penzo, Daniela Foti, Guidalberto ManfiolettiAbstract:Cancer heterogeneity is one of the factors that constitute an obstacle towards an efficient targeting of this multifaceted disease. Molecular information can help in classifying cancer subtypes and in providing clinicians with novel targeted therapeutic opportunities. In this regard, classification of breast cancer into intrinsic subtypes based on molecular profiling represents a valuable prototype. The High Mobility Group A (HMGA) chromatin architectural factors (HMGA1a, HMGA1b, and HMGA2) have a relevant and causal role in breast cancer onset and development, by influencing virtually all cancer hallmarks. The regulation of HMGA expression is under the control of major pathways involved in cell proliferation and survival, as well as in other cancer-related processes, thereby suggesting, for the HMGA members, a high degree of homology and overlapping activities. Despite of this evidence, HMGA proteins display also specific functions. In this review, we provide an overview of (i) the pathways involved in HMGA transcriptional and post-transcriptional regulation, (ii) the utilization of HMGA as molecular markers, and (iii) the biological role of HMGA in the context of breast cancer. We focus on the potential significance of HMGA in governing the onset and development of this tumour, as well as on the potential of these factors as novel specific targets for preventing and treating strategies. The emerging picture is a highly interconnected triad of proteins that could mutually influence each other, either in a competitive or cooperative manner, and that, in our opinion, should be considered as a unified and integrated protein system.
-
The HMGA gene family in chordates: evolutionary perspectives from amphioxus
Development Genes and Evolution, 2017Co-Authors: Matteo Bozzo, Riccardo Sgarra, Guidalberto Manfioletti, Simone Macrì, Daniela Calzia, Paola Ramoino, Thurston Lacalli, Robert Vignali, Mario Pestarino, Simona CandianiAbstract:High mobility group A proteins of vertebrates, HMGA1 and 2, are chromatin architectural factors involved in development, cell differentiation, and neoplastic transformation. Here, we characterize an amphioxus HMGA gene ortholog and analyze its expression. As a basal chordate, amphioxus is well placed to provide insights into the evolution of the HMGA gene family, particularly in the transition from invertebrates to vertebrates. Our phylogenetic analysis supports the basal position of amphioxus, echinoderm, and hemichordate HMGA sequences to those of vertebrate HMGA1 and HMGA2. Consistent with this, the genomic landscape around amphioxus HMGA shares features with both. Whole mount in situ hybridization shows that amphioxus HMGA mRNA is detectable from neurula stage onwards in both nervous and non-nervous tissues. This correlates with protein expression monitored immunocytochemically using antibodies against human HMGA2 protein, revealing especially high levels of expression in cells of the lamellar body, the amphioxus homolog of the pineal, suggesting that the gene may have, among its many functions, an evolutionarily conserved role in photoreceptor differentiation.
-
A novel mechanism of post-translational modulation of HMGA functions by the histone chaperone nucleophosmin
Scientific reports, 2015Co-Authors: Laura Arnoldo, Riccardo Sgarra, Eusebio Chiefari, Stefania Iiritano, Biagio Arcidiacono, Silvia Pegoraro, Ilenia Pellarin, Antonio Brunetti, Guidalberto ManfiolettiAbstract:High Mobility Group A are non-histone nuclear proteins that regulate chromatin plasticity and accessibility, playing an important role both in physiology and pathology. Their activity is controlled by transcriptional, post-transcriptional, and post-translational mechanisms. In this study we provide evidence for a novel modulatory mechanism for HMGA functions. We show that HMGAs are complexed in vivo with the histone chaperone nucleophosmin (NPM1), that this interaction requires the histone-binding domain of NPM1, and that NPM1 modulates both DNA-binding affinity and specificity of HMGAs. By focusing on two human genes whose expression is directly regulated by HMGA1, the Insulin receptor (INSR) and the Insulin-like growth factor-binding protein 1 (IGFBP1) genes, we demonstrated that occupancy of their promoters by HMGA1 was NPM1-dependent, reflecting a mechanism in which the activity of these cis-regulatory elements is directly modulated by NPM1 leading to changes in gene expression. HMGAs need short stretches of AT-rich nucleosome-free regions to bind to DNA. Therefore, many putative HMGA binding sites are present within the genome. Our findings indicate that NPM1, by exerting a chaperoning activity towards HMGAs, may act as a master regulator in the control of DNA occupancy by these proteins and hence in HMGA-mediated gene expression.
-
Expression and functional characterization of Xhmg-at-hook genes in Xenopus laevis.
PloS one, 2013Co-Authors: Simone Macrì, Elisa Maurizio, Riccardo Sgarra, Robert Vignali, Gloria Ros, Salvina Zammitti, Ornella Milani, Marco Onorati, Guidalberto ManfiolettiAbstract:High Mobility Group A proteins (HMGA1 and HMGA2) are architectural nuclear factors involved in development, cell differentiation, and cancer formation and progression. Here we report the cloning, developmental expression and functional analysis of a new multi-AT-hook factor in Xenopus laevis (XHMG-AT-hook) that exists in three different isoforms. Xhmg-at-hook1 and 3 isoforms, but not isoform 2, are expressed throughout the entire development of Xenopus, both in the maternal and zygotic phase. Localized transcripts are present in the animal pole in the early maternal phase; during the zygotic phase, mRNA can be detected in the developing central nervous system (CNS), including the eye, and in the neural crest. We show evidence that XHMG-AT-hook proteins differ from typical HMGA proteins in terms of their properties in DNA binding and in protein/protein interaction. Finally, we provide evidence that they are involved in early CNS development and in neural crest differentiation.
Francesco Esposito - One of the best experts on this subject based on the ideXlab platform.
-
Epigenetic Mechanisms Leading to Overexpression of HMGA Proteins in Human Pituitary Adenomas
Frontiers in medicine, 2015Co-Authors: D D'angelo, Francesco Esposito, Alfredo FuscoAbstract:Overexpression of the HMGA1 and HMGA2 proteins is a feature of all human pituitary adenoma subtypes. However, amplification and/or rearrangement of the HMGA2 have been described in human prolactinomas, but rarely in other pituitary subtypes, and no genomic amplification of HMGA1 was detected in pituitary adenomas. Here, we summarize the functional role of HMGA proteins in pituitary tumorigenesis and the epigenetic mechanisms contributing to HMGA overexpression in these tumors focusing on recent studies indicating a critical role of non coding RNAs in modulating HMGA protein levels.
-
HMGA1 pseudogene expression is induced in human pituitary tumors
Cell Cycle, 2015Co-Authors: Francesco Esposito, Marco De Martino, Daniela Dangelo, Paula Mussnich, M L Jaffrainrea, J. Trouillas, Filippo Fraggetta, Gerald Raverot, Alfredo FuscoAbstract:Numerous studies have established that High Mobility Group A (HMGA) proteins play a pivotal role on the onset of human pituitary tumors. They are overexpressed in pituitary tumors, and, consistently, transgenic mice overexpressing either the HMGA1 or the HMGA2 gene develop pituitary tumors. In contrast with HMGA2, HMGA1 overexpression is not related to any rearrangement or amplification of the HMGA1 locus in these tumors. We have recently identified 2 HMGA1 pseudogenes, HMGA1P6 and HMGA1P7, acting as competitive endogenous RNA decoys for HMGA1 and other cancer related genes. Here, we show that HMGA1 pseudogene expression significantly correlates with HMGA1 mRNA levels in growth hormone and nonfunctioning pituitary adenomas likely inhibiting the repression of HMGA1 through microRNAs action. According to our functional studies, these HMGA1 pseudogenes enhance the proliferation and migration of the mouse pituitary tumor cell line, at least in part, through their upregulation. Our results point out that the o...
-
HMGA1 pseudogenes as candidate proto oncogenic competitive endogenous rnas
Oncotarget, 2014Co-Authors: Francesco Esposito, Marco De Martino, Floriana Forzati, Giovanna Maria Pierantoni, Maria Grazia Petti, Mara Tornincasa, Antonella Federico, Claudio Arra, Alfredo FuscoAbstract:The High Mobility Group A (HMGA) are nuclear proteins that participate in the organization of nucleoprotein complexes involved in chromatin structure, replication and gene transcription. HMGA overexpression is a feature of human cancer and plays a causal role in cell transformation. Since non-coding RNAs and pseudogenes are now recognized to be important in physiology and disease, we investigated HMGA1 pseudogenes in cancer settings using bioinformatics analysis. Here we report the identification and characterization of two HMGA1 non-coding pseudogenes, HMGA1P6 and HMGA1P7. We show that their overexpression increases the levels of HMGA1 and other cancer-related proteins by inhibiting the suppression of their synthesis mediated by microRNAs. Consistently, embryonic fibroblasts from HMGA1P7-overexpressing transgenic mice displayed a higher growth rate and reduced susceptibility to senescence. Moreover, HMGA1P6 and HMGA1P7 were overexpressed in human anaplastic thyroid carcinomas, which are highly aggressive, but not in differentiated papillary carcinomas, which are less aggressive. Lastly, the expression of the HMGA1 pseudogenes was significantly correlated with HMGA1 protein levels thereby implicating HMGA1P overexpression in cancer progression. In conclusion, HMGA1P6 and HMGA1P7 are potential proto-oncogenic competitive endogenous RNAs.
-
The impairment of the High Mobility Group A (HMGA) protein function contributes to the anticancer activity of trabectedin.
European journal of cancer (Oxford England : 1990), 2012Co-Authors: D D'angelo, Francesco Esposito, Dario Palmieri, R Pacelli, Eleonora Borbone, Sarah Uboldi, Roberta Frapolli, Maurizio D'incalci, Alfredo FuscoAbstract:Abstract Trabectedin (Ecteinascidin-743 or ET-743) is a novel antitumour agent of marine origin with potent antitumour activity both in vitro and in vivo . It interacts with the minor groove of DNA, interfering with transcriptional activity and DNA repair pathways. Here, we report a novel mechanism by which trabectedin exerts its cytotoxic effects on carcinoma cells. It is based on its ability to impair the function of the High-Mobility Group A (HMGA) proteins. These proteins have a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. They bind the minor groove of DNA, alter chromatin structure and, thus, regulate the transcription of several genes by enhancing or suppressing the activity of transcription factors. We first report that trabectedin has a higher cytotoxic effect on thyroid and colon carcinoma cells expressing abundant levels of HMGAs in comparison with cells not expressing them. Then, we have shown that trabectedin treatment displaces HMGA proteins from the HMGA-responsive promoters, including ATM promoter, impairing their transcriptional activity. Finally, we report a synergism between Ionising Radiations and trabectedin treatment restricted to the HMGA-overexpressing cancer cells. This result might have important clinical implications since it would suggest the use of trabectedin for the treatment of neoplasias expressing abundant HMGA levels that are frequently associated to chemoresistance and poor prognosis.
-
PIT1 upregulation by HMGA proteins has a role in pituitary tumorigenesis
Endocrine-related cancer, 2012Co-Authors: Dario Palmieri, Francesco Esposito, Ivana De Martino, Anne Wierinckx, Paolo Cappabianca, Gaetano Lombardi, Annamaria Colao, Teresa Valentino, Michela Vitiello, J. TrouillasAbstract: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 of Gh, Prl, Ghrhr and Pit1 itself, playing a key role in pituitary gland development and physiology. Therefore, the aim of our study was to identify the role of Pit1 overexpression in pituitary tumour development induced by HMGA1B and HMGA2. First, we demonstrated that HMGA1B and HMGA2 directly interact with both PIT1 and its gene promoter in vivo, and that these proteins positively regulate Pit1 promoter activity, also co-operating with PIT1 itself. Subsequently, we showed, by colony-forming assays on two different pituitary adenoma cell lines, GH3 and aT3, that Pit1 overexpression increases pituitary cell proliferation. Finally, the expression analysis of HMGA1, HMGA2 and PIT1 in human pituitary adenomas of different histological types revealed a direct correlation between PIT1 and HMGA expression levels. Taken together, our data indicate a role of Pit1 upregulation by HMGA proteins in pituitary tumours. Endocrine-Related Cancer (2012) 19 123–135
Riccardo Sgarra - One of the best experts on this subject based on the ideXlab platform.
-
High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network.
International journal of molecular sciences, 2020Co-Authors: Riccardo Sgarra, D D'angelo, Silvia Pegoraro, Sara Petrosino, Gloria Ros, Rossella Zanin, Michela Sgubin, Sabrina Battista, Guidalberto ManfiolettiAbstract: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.
-
High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression.
Biochimica et biophysica acta. Reviews on cancer, 2018Co-Authors: Riccardo Sgarra, Eusebio Chiefari, Silvia Pegoraro, Antonio Brunetti, Gloria Ros, Carlotta Penzo, Daniela Foti, Guidalberto ManfiolettiAbstract:Cancer heterogeneity is one of the factors that constitute an obstacle towards an efficient targeting of this multifaceted disease. Molecular information can help in classifying cancer subtypes and in providing clinicians with novel targeted therapeutic opportunities. In this regard, classification of breast cancer into intrinsic subtypes based on molecular profiling represents a valuable prototype. The High Mobility Group A (HMGA) chromatin architectural factors (HMGA1a, HMGA1b, and HMGA2) have a relevant and causal role in breast cancer onset and development, by influencing virtually all cancer hallmarks. The regulation of HMGA expression is under the control of major pathways involved in cell proliferation and survival, as well as in other cancer-related processes, thereby suggesting, for the HMGA members, a high degree of homology and overlapping activities. Despite of this evidence, HMGA proteins display also specific functions. In this review, we provide an overview of (i) the pathways involved in HMGA transcriptional and post-transcriptional regulation, (ii) the utilization of HMGA as molecular markers, and (iii) the biological role of HMGA in the context of breast cancer. We focus on the potential significance of HMGA in governing the onset and development of this tumour, as well as on the potential of these factors as novel specific targets for preventing and treating strategies. The emerging picture is a highly interconnected triad of proteins that could mutually influence each other, either in a competitive or cooperative manner, and that, in our opinion, should be considered as a unified and integrated protein system.
-
The HMGA gene family in chordates: evolutionary perspectives from amphioxus
Development Genes and Evolution, 2017Co-Authors: Matteo Bozzo, Riccardo Sgarra, Guidalberto Manfioletti, Simone Macrì, Daniela Calzia, Paola Ramoino, Thurston Lacalli, Robert Vignali, Mario Pestarino, Simona CandianiAbstract:High mobility group A proteins of vertebrates, HMGA1 and 2, are chromatin architectural factors involved in development, cell differentiation, and neoplastic transformation. Here, we characterize an amphioxus HMGA gene ortholog and analyze its expression. As a basal chordate, amphioxus is well placed to provide insights into the evolution of the HMGA gene family, particularly in the transition from invertebrates to vertebrates. Our phylogenetic analysis supports the basal position of amphioxus, echinoderm, and hemichordate HMGA sequences to those of vertebrate HMGA1 and HMGA2. Consistent with this, the genomic landscape around amphioxus HMGA shares features with both. Whole mount in situ hybridization shows that amphioxus HMGA mRNA is detectable from neurula stage onwards in both nervous and non-nervous tissues. This correlates with protein expression monitored immunocytochemically using antibodies against human HMGA2 protein, revealing especially high levels of expression in cells of the lamellar body, the amphioxus homolog of the pineal, suggesting that the gene may have, among its many functions, an evolutionarily conserved role in photoreceptor differentiation.
-
A novel mechanism of post-translational modulation of HMGA functions by the histone chaperone nucleophosmin
Scientific reports, 2015Co-Authors: Laura Arnoldo, Riccardo Sgarra, Eusebio Chiefari, Stefania Iiritano, Biagio Arcidiacono, Silvia Pegoraro, Ilenia Pellarin, Antonio Brunetti, Guidalberto ManfiolettiAbstract:High Mobility Group A are non-histone nuclear proteins that regulate chromatin plasticity and accessibility, playing an important role both in physiology and pathology. Their activity is controlled by transcriptional, post-transcriptional, and post-translational mechanisms. In this study we provide evidence for a novel modulatory mechanism for HMGA functions. We show that HMGAs are complexed in vivo with the histone chaperone nucleophosmin (NPM1), that this interaction requires the histone-binding domain of NPM1, and that NPM1 modulates both DNA-binding affinity and specificity of HMGAs. By focusing on two human genes whose expression is directly regulated by HMGA1, the Insulin receptor (INSR) and the Insulin-like growth factor-binding protein 1 (IGFBP1) genes, we demonstrated that occupancy of their promoters by HMGA1 was NPM1-dependent, reflecting a mechanism in which the activity of these cis-regulatory elements is directly modulated by NPM1 leading to changes in gene expression. HMGAs need short stretches of AT-rich nucleosome-free regions to bind to DNA. Therefore, many putative HMGA binding sites are present within the genome. Our findings indicate that NPM1, by exerting a chaperoning activity towards HMGAs, may act as a master regulator in the control of DNA occupancy by these proteins and hence in HMGA-mediated gene expression.
-
Expression and functional characterization of Xhmg-at-hook genes in Xenopus laevis.
PloS one, 2013Co-Authors: Simone Macrì, Elisa Maurizio, Riccardo Sgarra, Robert Vignali, Gloria Ros, Salvina Zammitti, Ornella Milani, Marco Onorati, Guidalberto ManfiolettiAbstract:High Mobility Group A proteins (HMGA1 and HMGA2) are architectural nuclear factors involved in development, cell differentiation, and cancer formation and progression. Here we report the cloning, developmental expression and functional analysis of a new multi-AT-hook factor in Xenopus laevis (XHMG-AT-hook) that exists in three different isoforms. Xhmg-at-hook1 and 3 isoforms, but not isoform 2, are expressed throughout the entire development of Xenopus, both in the maternal and zygotic phase. Localized transcripts are present in the animal pole in the early maternal phase; during the zygotic phase, mRNA can be detected in the developing central nervous system (CNS), including the eye, and in the neural crest. We show evidence that XHMG-AT-hook proteins differ from typical HMGA proteins in terms of their properties in DNA binding and in protein/protein interaction. Finally, we provide evidence that they are involved in early CNS development and in neural crest differentiation.
Monica Fedele - One of the best experts on this subject based on the ideXlab platform.
-
Pituitary Adenoma: Role of HMGA Proteins
Tumors of the Central Nervous System Volume 10, 2012Co-Authors: Monica Fedele, Alfredo FuscoAbstract:Pituitary tumors are in most cases monoclonal adenomas arising from the adenohypophysial cells, and represent about 15% of intracranial tumors. They, while benign tumors, show a significant morbidity related to the endocrinological symptoms of hypo-or hyper-secretion of hormones and/or mass effect of the tumor on adjacent brain structures. Despite their considerable social impact, yet relatively little is known about the molecular events underlying pituitary tumorigenesis. Recent studies have demonstrated that the High Mobility Group A (HMGA) gene family, including HMGA1 and HMGA2, has a critical role in the development of pituitary adenomas. Indeed, the HMGA2 gene is amplified and overexpressed in several pituitary adenomas, and, consistently, transgenic mice overexpressing either HMGA1 or HMGA2 develop pituitary adenomas. The overxpression of the HMGA proteins would induce pituitary adenomas mainly by enhancing the activity of the transcription factor E2F1 and by upregulating the expression of cyclin B2 and other genes involved in the regulation of the cell cycle.
-
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, 2012Co-Authors: Monica Fedele, Giovanna Maria Pierantoni, Pierlorenzo Pallante, Alfredo FuscoAbstract: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
-
HMGA2 a pituitary tumour subtype specific oncogene
Molecular and Cellular Endocrinology, 2010Co-Authors: Monica Fedele, Dario Palmieri, Alfredo FuscoAbstract:The high mobility group AT-hook (HMGA) proteins, a family of DNA architectural factors, are highly expressed during embryogenesis and play a crucial role in several different biological processes, as well as in tumorigenesis of a wide range of tissues, including pituitary. Indeed, HMGA2 has been found rearranged and amplified in human prolactinomas, and transgenic mice overexpressing either HMGA1 or HMGA2 develop pituitary adenomas secreting prolactin and growth hormone. Here, we overview HMGA proteins in human tumours, focusing on pituitary adenomas and the mechanisms by which the HMGA proteins are involved in their onset and development. Different HMGA-dependent potential drives of pituitary oncogenesis are discussed as future research directions in the field.
-
HAND1 gene expression is negatively regulated by the High Mobility Group A1 proteins and is drastically reduced in human thyroid carcinomas
Oncogene, 2008Co-Authors: J Martinez Hoyos, Monica Fedele, Angelo Ferraro, I De Martino, Pierlorenzo Pallante, Eleonora Borbone, Silvana Sacchetti, Simona Keller, Donatella Montanaro, Francesco EspositoAbstract:HMGA1 proteins exert their major physiological function during embryonic development and play a critical role in neoplastic transformation. Here, we show that Hand1 gene, which codes for a transcription factor crucial for differentiation of trophoblast giant cells and heart development, is upregulated in HMGA1 minus embryonic stem cells. We demonstrate that HMGA1 proteins bind directly to Hand1 promoter both in vitro and in vivo and inhibit Hand1 promoter activity. We have also investigated HAND1 expression in human thyroid carcinoma cell lines and tissues, in which HMGA proteins are overexpressed, with respect to normal thyroid; an inverse correlation between HMGA1 and HAND1 expression was found in all thyroid tumor histotypes. A correlation between HAND1 gene repression and promoter hypermethylation was found in anaplastic carcinomas but not in other thyroid tumor histotypes. Therefore, we can hypothesize that HMGA1 overexpression plays a key role on HAND1 silencing in differentiated thyroid carcinomas and that promoter hypermethylation occurs in later stages of thyroid tumor progression. Finally, the restoration of the HAND1 gene expression reduces the clonogenic ability of two human thyroid carcinoma-derived cell lines, suggesting that HAND1 downregulation may have a role in the process of thyroid carcinogenesis.
-
Roles of HMGA proteins in cancer
Nature Reviews Cancer, 2007Co-Authors: Alfredo Fusco, Monica FedeleAbstract:The high mobility group A (HMGA) non-histone chromatin proteins alter chromatin structure and thereby regulate the transcription of several genes by either enhancing or suppressing transcription factors. This protein family is implicated, through different mechanisms, in both benign and malignant neoplasias. Rearrangements of HMGA genes are a feature of most benign human mesenchymal tumours. Conversely, unrearranged HMGA overexpression is a feature of malignant tumours and is also causally related to neoplastic cell transformation. Here, we focus on the role of the HMGA proteins in human neoplastic diseases, the mechanisms by which they contribute to carcinogenesis, and therapeutic strategies based on targeting HMGA proteins. High mobility group A (HMGA) proteins alter chromatin structure and therefore affect the transcription of large sets of genes. This can contribute to both benign and malignant disease in several ways. The high mobility group A (HMGA) family is composed of four proteins, HMGA1a, HMGA1b, HMGA1c and HMGA2, encoded by two distinct genes. HMGA1 proteins are products of the same gene, generated through alternative splicing. They are non-histone nuclear proteins known as 'architectural transcriptional factors'. HMGA gene rearrangements, due to chromosomal translocations, are a feature of human benign tumours of mesenchymal origin. In most of the cases the breakpoint occurs in the third intron of the HMGA2 gene, resulting in deregulation of its expression, truncation or, more frequently, in the generation of fusion genes encoding chimeric transcripts containing the first three exons of HMGA2 and ectopic sequences from other genes. HMGA protein overexpression is a constant feature of human malignant neoplasias. It represents a poor prognostic index as their overexpression often correlates with the presence of metastasis and with a reduced survival. HMGA proteins have a crucial role in cell transformation. They show oncogenic activities in vitro and in vivo , and blockage of their synthesis suppresses the malignant phenotype. The appearance of a neoplastic phenotype in HMGA1 ^−/− and HMGA1 ^+/− mice revealed that HMGA proteins also have a tumour suppressor function. HMGA proteins exert their oncogenic activity through several mechanisms: induction of E2F1 and AP1 activity, induction of cyclin A expression, inactivation of p53-induced apoptosis, impairment of DNA repair, enhancement of the expression of proteins involved in inflammation, and modulation of the expression of microRNAs and genes involved in epithelial–mesenchymal transition. Blocking HMGA function could be an excellent tool for cancer treatment because of the specificity, low toxicity and wide range of applications of such therapy.