Aatf
218556752
A Nomogram Based on a Three Gene Signature Derived from AATF Coexpressed Genes Predicts Overall Survival of Hepatocellular Carcinoma Patients
Background Hepatocellular carcinoma (HCC) is a common cancer with an extremely high mortality rate. Therefore, there is an urgent need in screening key biomarkers of HCC to predict the prognosis and develop more individual treatments. Recently, AATF is reported to be an important factor contributing to HCC. Methods We aimed to establish a gene signature to predict overall survival of HCC patients. Firstly, we examined the expression level of AATF in the Gene Expression Omnibus (GEO) the Cancer Genome Atlas (TCGA) and the International Union of Cancer Genome (ICGC) databases. Genes coexpressed with AATF were identified in the TCGA dataset by the Poisson correlation coefficient and used to establish a gene signature for survival prediction. The prognostic significance of this gene signature was then validated in the ICGC dataset and used to build a combined prognostic model for clinical practice. Results Gene expression data and clinical information of 2521 HCC patients were downloaded from three public databases. AATF expression in HCC tissue was higher than that in matched normal liver tissues. 644 genes coexpressed with AATF were identified by the Poisson correlation coefficient and used to establish a three gene signature (KIF20A, UCK2, and SLC41A3) by the univariate and multivariate least absolute shrinkage and selection operator Cox regression analyses. This three gene signature was then used to build a combined nomogram for clinical practice. Conclusion This integrated nomogram based on the three gene signature can predict overall survival for HCC patients well. The three gene signature may be a potential therapeutic target in HCC.
BioMed research international
Jinli Liu Jianjun Lu Zhanzhong Ma Wenli Li
218691295
Che 1/AATF binds to RNA polymerase I machinery and sustains ribosomal RNA gene transcription
Abstract Originally identified as an RNA polymerase II interactor, Che 1/AATF (Che 1) has now been recognized as a multifunctional protein involved in cell cycle regulation and cancer progression, as well as apoptosis inhibition and response to stress. This protein displays a peculiar nucleolar localization and it has recently been implicated in pre rRNA processing and ribosome biogenesis. Here, we report the identification of a novel function of Che 1 in the regulation of ribosomal RNA (rRNA) synthesis, in both cancer and normal cells. We demonstrate that Che 1 interacts with RNA polymerase I and nucleolar upstream binding factor (UBF) and promotes RNA polymerase I dependent transcription. Furthermore, this protein binds to the rRNA gene (rDNA) promoter and modulates its epigenetic state by contrasting the recruitment of HDAC1. Che 1 downregulation affects RNA polymerase I and UBF recruitment on rDNA and leads to reducing rDNA promoter activity and 47S pre rRNA production. Interestingly, Che 1 depletion induces abnormal nucleolar morphology associated with re distribution of nucleolar proteins. Finally, we show that upon DNA damage Che 1 re localizes from rDNA to TP53 gene promoter to induce cell cycle arrest. This previously uncharacterized function of Che 1 confirms the important role of this protein in the regulation of ribosome biogenesis, cellular proliferation and response to stress.
Nucleic acids research
Cristina Sorino Valeria Catena Tiziana Bruno Francesca De Nicola Stefano Scalera Gianluca Bossi Francesca Fabretti Miguel Mano Enrico De Smaele Maurizio Fanciulli Simona Iezzi
211018098
AATF and SMARCA2 are associated with thyroid volume in Hashimoto's thyroiditis patients
Thyroid volume of Hashimoto's thyroiditis (HT) patients varies in size over the course of disease and it may reflect changes in biological function of thyroid gland. Patients with subclinical hypothyroidism predominantly have increased thyroid volume whereas patients with more pronounced hypothyroidism have smaller thyroid volumes. Suggested mechanism for thyroid atrophy is thyrocyte death due to apoptosis. We performed the first genome wide association study (GWAS) of thyroid volume in two groups of HT patients, depending on levothyroxine (LT4) therapy, and then meta analysed across. Study included 345 HT patients in total and 6 007 322 common autosomal genetic variants. Underlying hypothesis was that genetic components that are involved in regulation of thyroid volume display their effect in specific pathophysiologic conditions of thyroid gland of HT patients. We additionally performed immunohistochemical analysis using thyroid tissues and analysed differences in expression levels of identified proteins and apoptotic marker between HT patients and controls. We found genome wide significant association of two loci, both involved in apoptosis, with thyroid volume of HT patients: rs7212416 inside apoptosis antagonizing transcription factor AATF (P 8.95 x 10 9 and rs10738556 near chromatin remodeling SMARCA2 (P 2.83 x 10 8 In immunohistochemical analysis we observed that HT patients with homozygous AATF risk genotypes have decreased AATF expression (0.46 fold, P 0.0001) and increased apoptosis (3.99 fold, P 0.0001) in comparison to controls. HT patients with heterozygous SMARCA2 genotypes have decreased SMARCA2 expression, albeit without reaching statistical significance (1.07 fold, P 0.5876) and significantly increased apoptosis (4.11 fold, P 0.0001) By two lines of evidence we show that two highly plausible genetic loci, AATF and SMARCA2 may be involved in determining the thyroid volume of HT patients. The results of our study significantly add to the current knowledge of disturbed biological mechanisms in thyroid gland of HT patients.
Scientific Reports
Luka Brcic Ana Baric Benjamin Benzon Marko Brekalo Sanda Gracan Dean Kalicanin Veselin Skrabic Tatijana Zemunik Maja Barbalic Ivana Novak Valdi Pesutic Pisac Ante Punda Vesna Boraska Perica
226948513
Che 1/AATF induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma.
Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che 1/AATF (Che 1) an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che 1 depletion leads to a reduction of "active chromatin" by inducing a global decrease of histone acetylation. In this context, Che 1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che 1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che 1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che 1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.
Blood advances
Tiziana Bruno Francesca De Nicola Giacomo Corleone Valeria Catena Frauke Goeman Matteo Pallocca Cristina Sorino Gianluca Bossi Bruno Amadio Giovanni Cigliana Maria Rosaria Ricciardi Maria Teresa Petrucci Enrico Pierluigi Spugnini Alfonso Baldi Mario Cioce Giancarlo Cortese Elisabetta Mattei Roberta Merola Umberto Gianelli Luca Baldini Francesco Pisani Svitlana Gumenyuk Andrea Mengarelli Katja Hopker Thomas Benzing Bruno Vincenzi Aristide Floridi Claudio Passananti Giovanni Blandino Simona Iezzi Maurizio Fanciulli
219547064
AATF/Che 1 An RNA Binding Protein at the Nexus of DNA Damage Response and Ribosome Biogenesis
The DNA damage response (DDR) is a complex signaling network that is activated upon genotoxic stress. It determines cellular fate by either activating cell cycle arrest or initiating apoptosis and thereby ensures genomic stability. The Apoptosis Antagonizing Transcription Factor (AATF/Che 1) an RNA polymerase II interacting transcription factor and known downstream target of major DDR kinases, affects DDR signaling by inhibiting p53 mediated transcription of pro apoptotic genes and promoting cell cycle arrest through various pathways instead. Specifically, AATF was shown to inhibit p53 expression at the transcriptional level and repress its pro apoptotic activity by direct binding to p53 protein and transactivation of anti apoptotic genes. Solid and hematological tumors of various organs exploit this function by overexpressing AATF. Both copy number gains and high expression levels of AATF were associated with worse prognosis or relapse of malignant tumors. Recently, a number of studies have enabled insights into the molecular mechanisms by which AATF affects both DDR and proliferation. AATF was found to directly localize to sites of DNA damage upon laser ablation and interact with DNA repair proteins. In addition, depletion of AATF resulted in increased DNA damage and decrease of both proliferative activity and genotoxic tolerance. Interestingly, considering the role of ribosomal stress in the regulation of p53, more recent work established AATF as ribosomal RNA binding protein and enabled insights into its role as an important factor for rRNA processing and ribosome biogenesis. This Mini Review summarizes recent findings on AATF and its important role in the DDR, malignancy, and ribosome biogenesis.
Frontiers in Oncology
Rainer W J Kaiser Johanna Erber Katja Hopker Francesca Fabretti Roman-Ulrich Muller
226248880
Emerging roles of AATF: Checkpoint signaling and beyond
Apoptosis antagonizing transcription factor (AATF) an interacting partner of RNA polymerase II is a multifunctional protein that is highly conserved in eukaryotes. In addition to the regulation of gene expression as a transcriptional coactivator, AATF is shown to play a dual role in regulating the cell cycle by displacing histone deacetylases 1 (HDAC1) from the retinoblastoma E2F transcription factor (Rb E2F) complex and also from the specificity protein 1 (Sp1) transcription factor responsible for p21 expression, thereby ensuring cell proliferation and growth arrest, respectively, at different checkpoints of the cell cycle. Notably, AATF has emerged as one of the most important modulators of various cellular responses such as proliferation, apoptosis, and survival. Studies have demonstrated that AATF protects cells from multiple stress stimuli such as DNA damage, ER stress, hypoxia, or glucose deprivation by inducing cell cycle arrest, autophagy, or apoptosis inhibition. Furthermore, AATF serves as a critical regulator in various cancers and promotes tumorigenesis by protecting cancer cells from apoptosis induction, favoring cell proliferation, or promoting cell survival by autophagy. Recent studies have demonstrated the key role of AATF in ribosome biosynthesis and have also provided insights into the mechanistic role of AATF, offering impressive cytoprotection in myocardial infarction, neurologic diseases, and nephronophthisis. In this review, we will provide a comprehensive overview of the role of AATF and shed light on its emerging roles underlining the potential use of AATF as a novel biomarker and as an effective therapeutic target.
Journal of cellular physiology
Akshatha N Srinivas Diwakar Suresh Faridoddin Mirshahi Prasanna K Santhekadur Arun J Sanyal Divya P Kumar
199000339
A protein RNA interaction atlas of the ribosome biogenesis factor AATF
AATF is a central regulator of the cellular outcome upon p53 activation, a finding that has primarily been attributed to its function as a transcription factor. Recent data showed that AATF is essential for ribosome biogenesis and plays a role in rRNA maturation. AATF has been implicated to fulfil this role through direct interaction with rRNA and was identified in several RNA interactome capture experiments. Here, we provide a first comprehensive analysis of the RNA bound by AATF using CLIP sequencing. Interestingly, this approach shows predominant binding of the 45S pre ribosomal RNA precursor molecules. Furthermore, AATF binds to mRNAs encoding for ribosome biogenesis factors as well as snoRNAs. These findings are complemented by an in depth analysis of the protein interactome of AATF containing a large set of proteins known to play a role in rRNA maturation with an emphasis on the protein RNA complexes known to be required for the generation of the small ribosomal subunit (SSU) In line with this finding, the binding sites of AATF within the 45S rRNA precursor localize in close proximity to the SSU cleavage sites. Consequently, our multilayer analysis of the protein RNA interactome of AATF reveals this protein to be an important hub for protein and RNA interactions involved in ribosome biogenesis.
Scientific Reports
Rainer W J Kaiser Michael Ignarski Eric L Van Nostrand Christian K Frese Manaswita Jain Sadrija Cukoski Heide Heinen Melanie Schaechter Lisa Seufert Konstantin Bunte Peter Frommolt Patrick Keller Mark Helm Katrin Bohl Martin Hohne Bernhard Schermer Thomas Benzing Katja Hopker Christoph Dieterich Gene W Yeo Roman-Ulrich Muller Francesca Fabretti
229286976
A protein RNA interaction atlas of the ribosome biogenesis factor AATF
ABSTRACT AATF is a central regulator of the cellular outcome upon p53 activation, a finding that has primarily been attributed to its function as a transcription factor. Recent data showed that AATF is essential for ribosome biogenesis and plays a role in rRNA maturation. AATF has been implicated to fulfil this role through direct interaction with rRNA and was identified in several RNA interactome capture experiments. Here, we provide a first comprehensive analysis of the RNA bound by AATF using CLIP sequencing. Interestingly, this approach shows predominant binding of the 45S pre ribosomal RNA precursor molecules. Furthermore, AATF binds to mRNAs encoding for ribosome biogenesis factors as well as snoRNAs. These findings are complemented by an in depth analysis of the protein interactome of AATF containing a large set of proteins known to play a role in rRNA maturation with an emphasis on the protein RNA complexes known to be required for the generation of the small ribosomal subunit (SSU) In line with this finding, the binding sites of AATF within the 45S rRNA precursor localize in close proximity to the SSU cleavage sites. Consequently, our multilayer analysis of the protein RNA interactome of AATF reveals this protein to be an important hub for protein and RNA interactions involved in ribosome biogenesis.
Rainer W J Kaiser Michael Ignarski Eric L Van Nostrand Christian K Frese Manaswita Jain Sadrija Cukoski Heide Heinen Melanie Schaechter Lisa Seufert Konstantin Bunte Peter Frommolt Patrick Keller Mark Helm Katrin Bohl Martin Hohne Bernhard Schermer Thomas Benzing Katja Hopker Christoph Dieterich Gene W Yeo Roman Ulrich Mueller Francesca Fabretti
196685542
PB1649 EXOSOMES MEDIATED DELIVERY OF RNA OLIGOS DIRECTED TO CHE 1/AATF IMPAIRS BCP ALL VITALITY
HemaSphere
Matteo Caforio Cristina Sorino Valentina Bertaina Angela Pitisci Giuseppe Battafarano Andrea Del Fattore Maurizio Fanciulli Valentina Folgiero F Locatelli
198293524
Supplement to: "AATF and SMARCA2 are associated with thyroid volume in Hashimoto's thyroiditis patients"
Vesna Boraska