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Jeffrey F. Krane - One of the best experts on this subject based on the ideXlab platform.

  • HMGA2 is a specific immunohistochemical marker for pleomorphic adenoma and carcinoma ex pleomorphic adenoma
    Histopathology, 2017
    Co-Authors: Jeffrey K. Mito, Simion I. Chiosea, Paola Dal Cin, Jeffrey F. Krane
    Abstract:

    Aims Accurate classification of salivary gland neoplasms may be challenging due to morphologic overlap, particularly in small biopsies. Recurrent translocations involving High Mobility Group A2 (HMGA2) are present in a subset of pleomorphic adenoma (PA) and carcinoma ex-pleomorphic adenoma (CA ex-PA). We evaluated immunohistochemical HMGA2 expression in 225 salivary gland tumors including 56 PAs, 37 CA ex-PAs and 132 potential histologic mimics to determine its diagnostic utility. Methods and results HMGA2 expression was identified in 19 PAs (33.9%) and 9 CA ex-PAs (24.3%). Expression was strong and diffuse throughout all PAs and 4 of 9 positive CA ex-PA cases. In 5 CA ex-PAs, HMGA2 showed weak-to-strong multifocal staining within the carcinomatous component, with strong, diffuse HMGA2 expression in residual PA. Among histologic mimics: 6 de novo salivary duct carcinomas (28.5%), 3 epithelial-myoepithelial carcinomas (33.3%) and 1 case each of myoepithelioma and basal cell adenoma expressed HMGA2. FISH for HMGA2 rearrangement performed on a subset of tumors showed diffuse HMGA2 expression in PA and CA ex-PA was frequently associated with rearrangement of the HMGA2 locus, while cases of de novo salivary duct carcinoma, or CA ex-PA with limited or no HMGA2 expression, had an intact HMGA2 locus. Conclusions HMGA2 expression is a highly specific (96.2%), but low sensitivity (29.8%), marker for PA and CA ex-PA when compared to histologic mimics, and is frequently associated with rearrangement of the HMGA2 locus. This article is protected by copyright. All rights reserved.

  • HMGA2 is a specific immunohistochemical marker for pleomorphic adenoma and carcinoma ex‐pleomorphic adenoma
    Histopathology, 2017
    Co-Authors: Jeffrey K. Mito, Paola Dal Cin, Simion I. Chiosea, Jeffrey F. Krane
    Abstract:

    Accurate classification of salivary gland neoplasms may be challenging, owing to morphological overlap, particularly in small biopsies. Recurrent translocations involving the high-mobility group AT-hook 2 (HMGA2) gene are present in a subset of pleomorphic adenomas (PAs) and carcinoma ex-pleomorphic adenomas (CA ex-PAs). The aim of this study was to evaluate immunohistochemical HMGA2 expression in 225 salivary gland tumours, including 56 PAs, 37 CA ex-PAs, and 132 potential histological mimics, to determine its diagnostic utility. HMGA2 expression was identified in 19 PAs (33.9%) and nine CA ex-PAs (24.3%). Expression was strong and diffuse throughout all PAs, and in four of nine positive CA ex-PAs. In five CA ex-PAs, HMGA2 showed weak-to-strong multifocal staining within the carcinomatous component, and strong diffuse HMGA2 expression in the residual PA. Among histological mimics, six de-novo salivary duct carcinomas (28.5%), three epithelial-myoepithelial carcinomas (33.3%) and one case each of myoepithelioma and basal cell adenoma expressed HMGA2. Fluorescence in-situ hybridization for HMGA2 rearrangement performed on a subset of tumours that showed diffuse HMGA2 expression in PAs and CA ex-PAs was frequently associated with rearrangement of the HMGA2 locus, whereas cases of de-novo salivary duct carcinoma, or CA ex-PA with limited or no HMGA2 expression, had an intact HMGA2 locus. HMGA2 expression is a highly specific (96.2%), but low-sensitivity (29.8%), marker for PA and CA ex-PA when compared with histological mimics, and is frequently associated with rearrangement of the HMGA2 locus. © 2017 John Wiley & Sons Ltd.

Jeffrey K. Mito - One of the best experts on this subject based on the ideXlab platform.

  • HMGA2 is a specific immunohistochemical marker for pleomorphic adenoma and carcinoma ex pleomorphic adenoma
    Histopathology, 2017
    Co-Authors: Jeffrey K. Mito, Simion I. Chiosea, Paola Dal Cin, Jeffrey F. Krane
    Abstract:

    Aims Accurate classification of salivary gland neoplasms may be challenging due to morphologic overlap, particularly in small biopsies. Recurrent translocations involving High Mobility Group A2 (HMGA2) are present in a subset of pleomorphic adenoma (PA) and carcinoma ex-pleomorphic adenoma (CA ex-PA). We evaluated immunohistochemical HMGA2 expression in 225 salivary gland tumors including 56 PAs, 37 CA ex-PAs and 132 potential histologic mimics to determine its diagnostic utility. Methods and results HMGA2 expression was identified in 19 PAs (33.9%) and 9 CA ex-PAs (24.3%). Expression was strong and diffuse throughout all PAs and 4 of 9 positive CA ex-PA cases. In 5 CA ex-PAs, HMGA2 showed weak-to-strong multifocal staining within the carcinomatous component, with strong, diffuse HMGA2 expression in residual PA. Among histologic mimics: 6 de novo salivary duct carcinomas (28.5%), 3 epithelial-myoepithelial carcinomas (33.3%) and 1 case each of myoepithelioma and basal cell adenoma expressed HMGA2. FISH for HMGA2 rearrangement performed on a subset of tumors showed diffuse HMGA2 expression in PA and CA ex-PA was frequently associated with rearrangement of the HMGA2 locus, while cases of de novo salivary duct carcinoma, or CA ex-PA with limited or no HMGA2 expression, had an intact HMGA2 locus. Conclusions HMGA2 expression is a highly specific (96.2%), but low sensitivity (29.8%), marker for PA and CA ex-PA when compared to histologic mimics, and is frequently associated with rearrangement of the HMGA2 locus. This article is protected by copyright. All rights reserved.

  • Prevalence and significance of HMGA2 expression in oesophageal adenocarcinoma.
    Histopathology, 2017
    Co-Authors: Jeffrey K. Mito, Agoston T. Agoston, Paola Dal Cin, Amitabh Srivastava
    Abstract:

    Aims Esophageal adenocarcinoma (EAC) tumorigenesis has been primarily linked to loss-of-function mutations in tumor suppressor genes. Knowledge of specific oncogenes that drive tumor progression, and their relationship to outcomes, is limited. High Mobility Group AT-Hook 2 (HMGA2) has been reported to be amplified in a subset of EACs, but the clinicopathologic and prognostic implications of HMGA2 expression in EAC is unknown. Methods and Results We performed HMGA2 immunohistochemistry and fluorescence in-situ hybridization (FISH) in EAC to determine its clinicopathologic and prognostic significance. Ninety-one primary EAC resections without neoadjuvant treatment were identified and immunohistochemistry for HMGA2 was performed. The presence or absence of nuclear staining was evaluated and correlated with predetermined clinicopathologic parameters and patient outcomes. A selected subset of tumors was subjected to FISH to identify alterations at the HMGA2 locus. HMGA2 expression was present in 25/91 (27.4%) tumors. HMGA2 expressing cells were present in solid, poorly differentiated areas of the tumors at the invasive front, or as single infiltrating cells. FISH showed that 3-4 copies of HMGA2 are frequently present in EAC irrespective of HMGA2 protein expression and that high level HMGA2 amplification is a rare event. HMGA2 expression was associated with numerous adverse clinicopathologic parameters including higher T- and N-stage, the presence of lymphovascular invasion, and with a worse recurrence free and overall survival. Conclusion Our data suggests that HMGA2 is primarily regulated in EAC through non-chromosomal level alterations that lead to increased HMGA2 expression. HMGA2 positive EAC correlates with adverse pathologic features and worse patient outcomes. This article is protected by copyright. All rights reserved.

  • HMGA2 is a specific immunohistochemical marker for pleomorphic adenoma and carcinoma ex‐pleomorphic adenoma
    Histopathology, 2017
    Co-Authors: Jeffrey K. Mito, Paola Dal Cin, Simion I. Chiosea, Jeffrey F. Krane
    Abstract:

    Accurate classification of salivary gland neoplasms may be challenging, owing to morphological overlap, particularly in small biopsies. Recurrent translocations involving the high-mobility group AT-hook 2 (HMGA2) gene are present in a subset of pleomorphic adenomas (PAs) and carcinoma ex-pleomorphic adenomas (CA ex-PAs). The aim of this study was to evaluate immunohistochemical HMGA2 expression in 225 salivary gland tumours, including 56 PAs, 37 CA ex-PAs, and 132 potential histological mimics, to determine its diagnostic utility. HMGA2 expression was identified in 19 PAs (33.9%) and nine CA ex-PAs (24.3%). Expression was strong and diffuse throughout all PAs, and in four of nine positive CA ex-PAs. In five CA ex-PAs, HMGA2 showed weak-to-strong multifocal staining within the carcinomatous component, and strong diffuse HMGA2 expression in the residual PA. Among histological mimics, six de-novo salivary duct carcinomas (28.5%), three epithelial-myoepithelial carcinomas (33.3%) and one case each of myoepithelioma and basal cell adenoma expressed HMGA2. Fluorescence in-situ hybridization for HMGA2 rearrangement performed on a subset of tumours that showed diffuse HMGA2 expression in PAs and CA ex-PAs was frequently associated with rearrangement of the HMGA2 locus, whereas cases of de-novo salivary duct carcinoma, or CA ex-PA with limited or no HMGA2 expression, had an intact HMGA2 locus. HMGA2 expression is a highly specific (96.2%), but low-sensitivity (29.8%), marker for PA and CA ex-PA when compared with histological mimics, and is frequently associated with rearrangement of the HMGA2 locus. © 2017 John Wiley & Sons Ltd.

Jian Jun Wei - One of the best experts on this subject based on the ideXlab platform.

  • HMGA2-mediated tumorigenesis through angiogenesis in leiomyoma
    Fertility and sterility, 2020
    Co-Authors: Wenan Qiang, Brannan B. Griffin, Tingting Gao, Debabrata Chakravarti, Serdar E. Bulun, J Julie Kim, Jian Jun Wei
    Abstract:

    Objective To study the role of HMGA2 in promoting angiogenesis in uterine leiomyoma (LM). Design This study involved evaluation of vessel density and angiogenic factors in leiomyomas with HMGA2 overexpression; examining angiogenic factor expression and AKT signaling in myometrial (MM) and leiomyoma cells by introducing HMGA2 overexpression in vitro; and exploring vessel formation induced by HMGA2 overexpression both in vitro and in vivo. Setting University research laboratory. Patients None. Interventions None. Main Outcome Measures The main outcome measures include vessel density in leiomyomas with HMGA2 (HMGA2-LM) or MED12 (MED12-LM) alteration; angiogenic factor expression in primary leiomyoma and in vitro cell line model; and vessel formation in leiomyoma cells with HMGA2 overexpression in vitro and in vivo. Results Angiogenic factors and receptors were significantly upregulated at mRNA and protein levels in HMGA2-LM. Specifically, HMGA2-LM exhibited increased expression of VEGFA, EGF, bFGF, TGFα, VEGFR1, and VEGFR2 compared to MED12-LM and myometrium. Overexpression of HMGA2 in MM and LM cell lines resulted in increased secretion of angiogenesis-associated factors. Secreted factors promoted human umbilical vein endothelial cell (HUVEC) migration, tube formation, and wound healing. HMGA2 overexpression upregulated IGF2BP2 and pAKT, and silencing the IGF2BP2 gene reduced pAKT levels and reduced HUVEC migration. Myometrial cells with stable HMGA2 overexpression exhibited increased colony formation and cell growth in vitro and formed xenografts with increased blood vessels. Conclusions HMGA2-LM have a high vasculature density, which likely contributes to tumor growth and disease burden of this leiomyoma subtype. HMGA2 plays an important role in angiogenesis and the involvement of IGF2BP2-mediated pAKT activity in angiogenesis, which provides a potential novel target for therapy for this subtype of LM.

  • HMGA2 overexpression induced ovarian surface epithelial transformation is mediated through regulation of emt genes
    Cancer Research, 2011
    Co-Authors: Zhaojian Liu, Peng Lee, Changshun Shao, Yaoqin Gong, Eva Hernando, Masashi Narita, William A Muller, Jinsong Liu, Jian Jun Wei
    Abstract:

    The AT-hook transcription factor HMGA2 is an oncogene involved in the tumorigenesis of many malignant neoplasms. HMGA2 overexpression is common in both early and late-stage high-grade ovarian serous papillary carcinoma. To test whether HMGA2 participates in the initiation of ovarian cancer and promotion of aggressive tumor growth, we examined the oncogenic properties of HMGA2 in ovarian surface epithelial (OSE) cell lines. We found that introduction of HMGA2 overexpression was sufficient to induce OSE transformation in vitro. HMGA2-mediated OSE transformation resulted in tumor formation in the xenografts of nude mice. By silencing HMGA2 in HMGA2-overexpressing OSE and ovarian cancer cell lines, the aggressiveness of tumor cell growth behaviors was partially suppressed. Global gene profiling analyses revealed that HMGA2-mediated tumorigenesis was associated with expression changes of target genes and microRNAs that are involved in epithelial-to-mesenchymal transition (EMT). Lumican, a tumor suppressor that inhibits EMT, was found to be transcriptionally repressed by HMGA2 and was frequently lost in human high-grade serous papillary carcinoma. Our findings show that HMGA2 overexpression confers a powerful oncogenic signal in ovarian cancers through the modulation of EMT genes.

  • HMGA2 : A biomarker significantly overexpressed in high-grade ovarian serous carcinoma
    Modern pathology : an official journal of the United States and Canadian Academy of Pathology Inc, 2010
    Co-Authors: Aparna Mahajan, Zhaojian Liu, Lan Lin Gellert, Xuanyi Zou, Guang Yu Yang, Peng Lee, Ximing J. Yang, Jian Jun Wei
    Abstract:

    Ovarian carcinoma consists of a group of histologically heterogeneous diseases involving distinct tumorigenic pathways. High-grade papillary serous carcinoma of the ovary is commonly associated with p53 mutations. HMGA2, an oncofetal protein, is found to be overexpressed in ovarian cancer. To study the function of HMGA2 in ovarian cancer, it is important to know which subtypes of ovarian cancer are associated with HMGA2 overexpression. In this study, we collected six different types of ovarian cancer and examined HMGA2 expression by immunohistochemistry, along with HMGA1, p53 and Ki-67. We found that HMGA2 overexpression was significantly higher in high-grade papillary serous carcinoma (64%) and carcinosarcoma (60%) than in other types of ovarian cancers (7–23%). HMGA2 overexpression was moderately associated with dominant p53 mutations (R=0.51). In addition, the microRNA in situ analysis revealed that let-7b, the HMGA2-negative regulators, were significantly lost in high-grade serous carcinoma. Our findings suggest that HMGA2 is an important molecular change significantly related to high-grade papillary serous carcinoma and is less common in other histological types of ovarian cancer.

  • Let-7 repression leads to HMGA2 overexpression in uterine leiomyosarcoma.
    Journal of cellular and molecular medicine, 2008
    Co-Authors: Guizhi Shi, Xuanyi Zou, Peng Lee, Eva Hernando, Masashi Narita, Mary Ann Perle, Khush Mittal, Hua Chen, Jian Jun Wei
    Abstract:

    Overexpression of HMGA2 is common in uterine leiomyomas (ULM). The expression of HMGA2 in its malignant counterpart – uterine leiomyosarcomas (ULMS) remains undetermined. Recently it has been shown that repression of HMGA2 by microRNA let-7s is a critical molecular regulatory mechanism associated with tumour growth in many tumours and cell types, including leiomyomas. To test whether HMGA2 and let-7s play a role in ULMS, we examined the levels of endogenous HMGA2 and let-7 expression and found a significant correlation between these two molecules in a case-matched cohort of human ULMS. We found that overexpression of HMGA2 and let-7-mediated HMGA2 repression is a relevant molecular alteration in ULMS. Disrupting the control of HMGA2 and let-7 pairs promotes ULMS cell growth in vitro.

Alfredo Fusco - One of the best experts on this subject based on the ideXlab platform.

  • HMGA2 overexpression plays a critical role in the progression of esophageal squamous carcinoma.
    Oncotarget, 2016
    Co-Authors: Antonio Palumbo, Alfredo Fusco, Nathalia Meireles Da Costa, Francesco Esposito, Marco De Martino, Daniela D'angelo, Vanessa Paiva Leite De Sousa, Ivanir Martins, Luiz Eurico Nasciutti, Luis Felipe Ribeiro Pinto
    Abstract:

    Esophageal Squamous Cell Carcinoma (ESCC) is the most common esophageal tumor worldwide. However, there is still a lack of deeper knowledge about biological alterations involved in ESCC development. High Mobility Group A (HMGA) protein family has been related with poor outcome and malignant cell transformation in several tumor types. In this way, the aim of this study was to analyze the expression of HMGA1 and HMGA2 expression in ESCC and their role in crucial cellular features. We evaluated HMGA1 and HMGA2 mRNA expression in 52 paired ESCC and normal surrounding tissue samples by qRT-PCR. Here, we show that HMGA2, but not HMGA1, is overexpressed in ESCC samples. This result was further confirmed by the immunohistochemical analysis. Indeed, accordingly to mRNA expression data, HMGA2, but not HMGA1, was overexpressed in approximately 90% of ESCC samples, while it was barely expressed in the respective control. Conversely, HMGA1, but not HMGA2, was overexpressed in esophageal adenocarcinoma samples. Interestingly, HMGA2 abrogation attenuated the malignant phenotype of two ESCC cell lines, suggesting that HMGA2 overexpression is involved in ESCC progression.

  • hmga1 and HMGA2 protein expression correlates with advanced tumour grade and lymph node metastasis in pancreatic adenocarcinoma
    Histopathology, 2012
    Co-Authors: Salvatore Piscuoglio, Alfredo Fusco, Francesco Esposito, Inti Zlobec, Pierlorenzo Pallante, Romina Sepe, Arthur Zimmermann, Ioannis Diamantis, Luigi Terracciano, Eva Karamitopoulou
    Abstract:

    Pancreatic ductal adenocarcinoma follows a multistep model of progression through precursor lesions called pancreatic intraepithelial neoplasia (PanIN). The high mobility group A1 (HMGA1) and high mobility group A2 (HMGA2) proteins are architectural transcription factors that have been implicated in the pathogenesis and progression of malignant tumours, including pancreatic cancer. The aim of this study was to explore the role of HMGA1 and HMGA2 in pancreatic carcinogenesis.

  • HMGA2 a pituitary tumour subtype specific oncogene
    Molecular and Cellular Endocrinology, 2010
    Co-Authors: Monica Fedele, Dario Palmieri, Alfredo Fusco
    Abstract:

    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.

  • Identification of new high mobility group A1 associated proteins.
    Proteomics, 2007
    Co-Authors: Giovanna Maria Pierantoni, Francesco Esposito, Stéphane Giraud, Willy Vincent Bienvenut, Jean Jacques Diaz, Alfredo Fusco
    Abstract:

    High mobility group A (HMGA) proteins (HMGA1a, HMGA1b, HMGA1c and HMGA2) are nonhistone chromosomal proteins that do not have transcriptional activity per se, but they orchestrate the assembly of multiprotein complexes involved in gene transcription, replication and chromatin structure through a complex network of protein-DNA and protein-protein interactions. To better understand their mechanisms of action, we have used a combination of coimmunoprecipitation, 1-D gel SDS-PAGE and MS to identify new potential molecular interactors. We have found 11 proteins that associate with HMGA1. These proteins belong to three different classes: mRNA processing proteins, RNA helicases and protein chaperones. Some interactions were confirmed by coimmunoprecipitation and pull-down experiments in human embryonal kidney 293 cells. These experimental data suggest that HMGA1 proteins can associate with proteins that are strictly involved in chromatin structure and in several important mRNA processing steps, supporting the idea that HMGA1 proteins can also participate in these events.

  • high mobility group a2 gene expression is frequently induced in non functioning pituitary adenomas nfpas even in the absence of chromosome 12 polysomy
    Endocrine-related Cancer, 2005
    Co-Authors: Giovanna Maria Pierantoni, Alfredo Fusco, Francesco Esposito, Palma Finelli, Emanuele Valtorta, Daniela Giardino, Ornella Rodeschini, Marco Losa, Lidia Larizza
    Abstract:

    The high-mobility group A2 (HMGA2) gene has a critical role in benign tumors where it is frequently rearranged, and in malignant tumors, where it is overexpressed in the absence of structural modification of the HMGA2 locus. By previous fluorescence in situ hybridization (FISH) and reverse transcriptase PCR analyses on human prolactin-secreting pituitary adenomas we detected rearrangement of the HMGA2 gene and amplification of its native region associated with activated expression. These data indicated a role for the HMGA2 gene in the development of human pituitary prolactinomas, since they are consistent with the appearance of prolactin/growth hormone adenomas in transgenic mice overexpressing the HMGA2 gene. To assess a more general role for HMGA2 in pituitary oncogenesis, we investigated HMGA2 amplification and expression in a panel of non-functioning pituitary adenomas (NFPAs) which account for 25% of all pituitary adenomas. We provide evidence that out of 18 NFPA tumors tested, 12 expressed HMGA2, but, different from prolactinomas, only in two cases the upregulation of the gene could be associated with amplification and/or rearrangement of the HMGA2 locus. Increased dosage of chromosome 12 was found in the expressing and non-expressing NFPAs, confirming that this sole event is insufficient to drive up activation of the HMGA2 gene. A role for chromosome 12 polysomy to promote structural instability of HMGA2 is confirmed, but the mechanism via trisomy is less prevalent in the frequently diploid NFPAs than in the usually hyperdiploid prolactinomas. Micro-rearrangements of HMGA2 gene not detectable by FISH analysis and/or sequence alterations could contribute to upregulation of HMGA2 gene in pituitary adenomas of the NFPA subtype. However, it cannot be excluded that the HMGA2 overexpression may be due, in some NFPA patients, to the same, still mainly unknown, mechanisms responsible for HMGA2 overexpression in malignant neoplasias.

Peter Droge - One of the best experts on this subject based on the ideXlab platform.

  • Effects of DNA Structural and Topological Constraints on HMGA2 Binding
    Biophysical Journal, 2015
    Co-Authors: Xiaodan Zhao, Peter Droge, Jie Yan
    Abstract:

    HMGA proteins belong to the super family of the high mobility group (HMG) proteins act as architectural transcription factors. They are known to modulate transcription of many genes by altering the chromatin structure. Recently, a new function of HMGA2 working as a replication fork chaperone has been uncovered and this finding implies the HMGA2 might recognize the particular fork structure during DNA replication. In order to gain insights of how HMGA2 interacts of DNA forks, we performed single-DNA manipulation studies of the binding of HMGA2 to DNA under various DNA structural and topological constraints such as DNA fork with three DNA arms, supercoiled DNA, DNA hairpins, and ssDNA. Ours results show that HMGA2 preferentially binds to supercoiled and forked DNA comparing to torsion unconstrained DNA and it has the least binding affinity to single-stranded template. The AT-hook DNA-binding domains in HMGA2 are critical form binding - removal of two of the three AT-hooks completely abolishes the binding. In conclusion, our studies show that HMGA proteins recognize structure rather than specific nucleotide sequences for binding via their unique AT-hook binding domains.

  • HMGA2 exhibits drp ap site cleavage activity and protects cancer cells from dna damage induced cytotoxicity during chemotherapy
    Nucleic Acids Research, 2009
    Co-Authors: Heike Summer, Lihong Zhan, Sabrina Peter, Padmapriya Sathiyanathan, Dana Henderson, Steven D Goodman, Thomas Klonisch, Ou Li, Peter Droge
    Abstract:

    HMGA proteins are not translated in normal human somatic cells, but are present in high copy numbers in pluripotent embryonic stem cells and most neoplasias. Correlations between the degree of malignancy, patient prognostic index and HMGA levels have been firmly established. Intriguingly, HMGA2 is also found in rare tumor-inducing cells which are resistant to chemotherapy. Here, we demonstrate that HMGA1a/b and HMGA2 possess intrinsic dRP and AP site cleavage activities, and that lysines and arginines in the AT-hook DNA-binding domains function as nucleophiles. We also show that HMGA2 can be covalently trapped at genomic abasic sites in cancer cells. By employing a variety of cell-based assays, we provide evidence that the associated lyase activities promote cellular resistance against DNA damage that is targeted by base excision repair (BER) pathways, and that this protection directly correlates with the level of HMGA2 expression. In addition, we demonstrate an interaction between human AP endonuclease 1 and HMGA2 in cancer cells, which supports our conclusion that HMGA2 can be incorporated into the cellular BER machinery. Our study thus identifies an unexpected role for HMGA2 in DNA repair in cancer cells which has important clinical implications for disease diagnosis and therapy.

  • the high mobility group protein HMGA2 a co regulator of chromatin structure and pluripotency in stem cells
    Stem Cell Reviews and Reports, 2009
    Co-Authors: Kurt Pfannkuche, Heike Summer, Jurgen Hescheler, Peter Droge
    Abstract:

    The small, chromatin-associated HMGA proteins contain three separate DNA binding domains, so-called AT hooks, which bind preferentially to short AT-rich sequences. These proteins are abundant in pluripotent embryonic stem (ES) cells and most malignant human tumors, but are not detectable in normal somatic cells. They act both as activator and repressor of gene expression, and most likely facilitate DNA architectural changes during formation of specialized nucleoprotein structures at selected promoter regions. For example, HMGA2 is involved in transcriptional activation of certain cell proliferation genes, which likely contributes to its well-established oncogenic potential during tumor formation. However, surprisingly little is known about how HMGA proteins bind DNA packaged in chromatin and how this affects the chromatin structure at a larger scale. Experimental evidence suggests that HMGA2 competes with binding of histone H1 in the chromatin fiber. This could substantially alter chromatin domain structures in ES cells and contribute to the activation of certain transcription networks. HMGA2 also seems capable of recruiting enzymes directly involved in histone modifications to trigger gene expression. Furthermore, it was shown that multiple HMGA2 molecules bind stably to a single nucleosome core particle whose structure is known. How these features of HMGA2 impinge on chromatin organization inside a living cell is unknown. In this commentary, we propose that HMGA2, through the action of three independent DNA binding domains, substantially contributes to the plasticity of ES cell chromatin and is involved in the maintenance of a un-differentiated cell state.

  • HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy.
    Nucleic Acids Research, 2009
    Co-Authors: Heike Summer, Lihong Zhan, Sabrina Peter, Padmapriya Sathiyanathan, Dana Henderson, Steven D Goodman, Thomas Klonisch, Ou Li, Peter Droge
    Abstract:

    HMGA proteins are not translated in normal human somatic cells, but are present in high copy numbers in pluripotent embryonic stem cells and most neoplasias. Correlations between the degree of malignancy, patient prognostic index and HMGA levels have been firmly established. Intriguingly, HMGA2 is also found in rare tumor-inducing cells which are resistant to chemotherapy. Here, we demonstrate that HMGA1a/b and HMGA2 possess intrinsic dRP and AP site cleavage activities, and that lysines and arginines in the AT-hook DNA-binding domains function as nucleophiles. We also show that HMGA2 can be covalently trapped at genomic abasic sites in cancer cells. By employing a variety of cell-based assays, we provide evidence that the associated lyase activities promote cellular resistance against DNA damage that is targeted by base excision repair (BER) pathways, and that this protection directly correlates with the level of HMGA2 expression. In addition, we demonstrate an interaction between human AP endonuclease 1 and HMGA2 in cancer cells, which supports our conclusion that HMGA2 can be incorporated into the cellular BER machinery. Our study thus identifies an unexpected role for HMGA2 in DNA repair in cancer cells which has important clinical implications for disease diagnosis and therapy.