Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53

Desantis, Agata; Bruno, Tiziana; Catena, Valeria; Nicola, Francesca De; Goeman, Frauke; Iezzi, Simona; Socolovschi, Cristina; Gentileschi, Maria Pia; Germoni, Sabrina; Monteleone, Valentina; Pellegrino, Marsha; Kann, Martin; Meo, Paolo D’Onorio De; Pallocca, Matteo; Höpker, Katja; Moretti, Fabiola; Mattei, Elisabetta; Reinhardt, Hans Christian; Floridi, Aristide; Passananti, Claudio; Benzing, Thomas; Blandino, Giovanni; Fanciulli, Maurizio

doi:10.1038/cddis.2015.117

Cited by 36 publications

(37 citation statements)

References 37 publications

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“…AATF, also called che‐1, is a transcriptional factor that is highly conserved among eukaryotes . AATF is known to promote cell proliferation and also survival by inducing cell cycle arrest, autophagy, DNA repair, and inhibition of apoptosis . Recent studies have shown that AATF is up‐regulated in breast and lung cancer and leukemia .…”

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“…(11,12) AATF is known to promote cell proliferation and also survival by inducing cell cycle arrest, autophagy, DNA repair, and inhibition of apoptosis. (13)(14)(15)(16)(17) Recent studies have shown that AATF is up-regulated in breast and lung cancer and leukemia. (18)(19)(20) The role of AATF in HCC in the setting of NAFLD and the associated molecular mechanisms were not known.…”

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A Regulatory Role of Apoptosis Antagonizing Transcription Factor in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

et al. 2019

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Hepatocellular carcinoma (HCC) is increasing as a cause of liver‐related mortality largely because of the growing burden of nonalcoholic steatohepatitis (NASH). The mechanisms of HCC development in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. We initially identified apoptosis antagonizing transcription factor (AATF) to be associated with HCC in a mouse model of NASH that develops HCC without the addition of specific carcinogens. AATF, also called che‐1, is a transcriptional factor that is highly conserved among eukaryotes. AATF is known to be a central mediator of the cellular responses as it promotes cell proliferation and survival by inducing cell cycle arrest, autophagy, DNA repair, and inhibition of apoptosis. However, the role of AATF in NASH and HCC remains unknown. Here, we provide evidence for AATF as a contributory factor for HCC in NAFLD. AATF overexpression was further verified in human NASH and HCC and multiple human HCC cell lines. Tumor necrosis factor‐α (TNFα), known to be increased in NASH, induced AATF expression. Promoter analysis of AATF revealed a sterol regulatory element binding transcription factor 1‐c (SREBP‐1c) binding site; inhibition of SREBP‐1 by using specific inhibitors as well as small interfering RNA decreased TNFα‐induced AATF expression. AATF interacted with signal transducer and activator of transcription 3 to increase monocyte chemoattractant protein‐1 expression. AATF knockdown decreased cell proliferation, migration, invasion, colony formation, and anchorage‐dependent growth in HCC cell lines. Xenograft of QGY‐7703 HCC cells with AATF stably knocked down into nonobese diabetic scid gamma mice demonstrated reduced tumorigenesis and metastases. Conclusion: AATF drives NAFLD and hepatocarcinogenesis, offering a potential target for therapeutic intervention.

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A Regulatory Role of Apoptosis Antagonizing Transcription Factor in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

et al. 2019

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“…Importantly, we show that the function of AATF in ribosome synthesis is independent of p53. Still, the described role of AATF as a transcriptional regulator and p53 interactor (71) is highly interesting in light of the fact that ribosome synthesis and cellular stress response pathways are strongly interwoven. Defects in ribosome synthesis, often referred to as ‘nucleolar stress’, are known to elicit p53 stabilization by a post-transcriptional mechanism.…”

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confidence: 99%

Human AATF/Che-1 forms a nucleolar protein complex with NGDN and NOL10 required for 40S ribosomal subunit synthesis

Bammert

Jonas

Ungricht

et al. 2016

Nucleic Acids Research

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Mammalian AATF/Che-1 is essential for embryonic development, however, the underlying molecular mechanism is unclear. By immunoprecipitation of human AATF we discovered that AATF forms a salt-stable protein complex together with neuroguidin (NGDN) and NOL10, and demonstrate that the AATF-NGDN-NOL10 (ANN) complex functions in ribosome biogenesis. All three ANN complex members localize to nucleoli and display a mutual dependence with respect to protein stability. Mapping of protein-protein interaction domains revealed the importance of both the evolutionary conserved WD40 repeats in NOL10 and the UTP3/SAS10 domain in NGDN for complex formation. Functional analysis showed that the ANN complex supports nucleolar steps of 40S ribosomal subunit biosynthesis. All complex members were required for 18S rRNA maturation and their individual depletion affected the same nucleolar cleavage steps in the 5′ETS and ITS1 regions of the ribosomal RNA precursor. Collectively, we identified the ANN complex as a novel functional module supporting the nucleolar maturation of 40S ribosomal subunits. Our data help to explain the described role of AATF in cell proliferation during mouse development as well as its requirement for malignant tumor growth.

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“…This binding occurs at the early stage of the DDR and specifically directs p53 toward the transcription of genes involved in cell cycle arrest. Notably, the two proteins detach when DNA damage is not repairable and cells undergo apoptosis ( Desantis et al, 2015a ). Evidence also shows that upon DNA damage phosphorylated-Che-1/AATF, by ATM and Chk2, promotes the transcription of the anti-apoptotic factor XIAP, an inhibitor of caspase activity.…”

Section: Che-1/aatf Is Involved In the Cellular Response To Differentmentioning

confidence: 99%

Discovering Che-1/AATF: a new attractive target for cancer therapy

Iezzi¹,

Fanciulli²

2015

Front. Genet.

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The transcriptional cofactor Che-1/AATF is currently emerging as an important component of the DNA damage response (DDR) machinery, the complex signaling network that maintains genome integrity and prevents tumorigenesis. Moreover this protein is involved in a wide range of cellular pathways, regulating proliferation and survival in both physiological and pathological conditions. Notably, some evidence indicates that dysregulation of Che-1/AATF levels are associated with the transformation process and elevated levels of Che-1/AATF are required for tumor cell survival. It is for these reasons that Che-1/AATF has been regarded as an attractive, still theoretical, therapeutic target for cancer treatments. In this review, we will provide an updated overview of Che-1/AATF activities, from transcriptional regulation to DDR.

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Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53

Cited by 36 publications

References 37 publications

A Regulatory Role of Apoptosis Antagonizing Transcription Factor in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

A Regulatory Role of Apoptosis Antagonizing Transcription Factor in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

Human AATF/Che-1 forms a nucleolar protein complex with NGDN and NOL10 required for 40S ribosomal subunit synthesis

Discovering Che-1/AATF: a new attractive target for cancer therapy

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