دورية أكاديمية
أعرض في EDS

Epigenetically silenced apoptosis-associated tyrosine kinase (AATK) facilitates a decreased expression of Cyclin D1 and WEE1, phosphorylates TP53 and reduces cell proliferation in a kinase-dependent manner.

التفاصيل البيبلوغرافية
العنوان: Epigenetically silenced apoptosis-associated tyrosine kinase (AATK) facilitates a decreased expression of Cyclin D1 and WEE1, phosphorylates TP53 and reduces cell proliferation in a kinase-dependent manner.
المؤلفون: Woods ML; Institute for Genetics, Justus-Liebig-University Giessen, 35392, Giessen, Germany., Weiss A; Department of Internal Medicine, Justus-Liebig-University Giessen, 35392, Giessen, Germany.; German Center for Lung Research (DZL), Giessen, Germany., Sokol AM; Scientific Service Group Biomolecular Mass Spectrometry, Max-Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany., Graumann J; Scientific Service Group Biomolecular Mass Spectrometry, Max-Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.; Institute for Translational Proteomics, Department of Medicine, Philipps-University, 35037, Marburg, Germany., Boettger T; Max-Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany., Richter AM; Institute for Genetics, Justus-Liebig-University Giessen, 35392, Giessen, Germany., Schermuly RT; Department of Internal Medicine, Justus-Liebig-University Giessen, 35392, Giessen, Germany.; German Center for Lung Research (DZL), Giessen, Germany., Dammann RH; Institute for Genetics, Justus-Liebig-University Giessen, 35392, Giessen, Germany. reinhard.dammann@gen.bio.uni-giessen.de.; German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center, 35392, Giessen, Germany. reinhard.dammann@gen.bio.uni-giessen.de.
المصدر: Cancer gene therapy [Cancer Gene Ther] 2022 Dec; Vol. 29 (12), pp. 1975-1987. Date of Electronic Publication: 2022 Jul 28.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9432230 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5500 (Electronic) Linking ISSN: 09291903 NLM ISO Abbreviation: Cancer Gene Ther Subsets: MEDLINE
أسماء مطبوعة: Publication: <2002->: London : Nature Publishing Group
Original Publication: Norwalk, CT : Appleton & Lange, c1994-
مواضيع طبية MeSH: Adenocarcinoma* , Pancreatic Neoplasms* , Protein-Tyrosine Kinases*/genetics , Protein-Tyrosine Kinases*/metabolism , Apoptosis Regulatory Proteins*/genetics , Apoptosis Regulatory Proteins*/metabolism, Humans ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation/genetics ; Cyclin D1/genetics ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Pancreatic Neoplasms
مستخلص: Silencing of the Apoptosis associated Tyrosine Kinase gene (AATK) has been described in cancer. In our study, we specifically investigated the epigenetic inactivation of AATK in pancreatic adenocarcinoma, lower grade glioma, lung, breast, head, and neck cancer. The resulting loss of AATK correlates with impaired patient survival. Inhibition of DNA methyltransferases (DNMTs) reactivated AATK in glioblastoma and pancreatic cancer. In contrast, epigenetic targeting via the CRISPR/dCas9 system with either EZH2 or DNMT3A inhibited the expression of AATK. Via large-scale kinomic profiling and kinase assays, we demonstrate that AATK acts a Ser/Thr kinase that phosphorylates TP53 at Ser366. Furthermore, whole transcriptome analyses and mass spectrometry associate AATK expression with the GO term 'regulation of cell proliferation'. The kinase activity of AATK in comparison to the kinase-dead mutant mediates a decreased expression of the key cell cycle regulators Cyclin D1 and WEE1. Moreover, growth suppression through AATK relies on its kinase activity. In conclusion, the Ser/Thr kinase AATK represses growth and phosphorylates TP53. Furthermore, expression of AATK was correlated with a better patient survival for different cancer entities. This data suggests that AATK acts as an epigenetically inactivated tumor suppressor gene.
(© 2022. The Author(s).)
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المشرفين على المادة: 0 (Cell Cycle Proteins)
136601-57-5 (Cyclin D1)
EC 2.7.10.1 (Protein-Tyrosine Kinases)
0 (TP53 protein, human)
0 (Tumor Suppressor Protein p53)
EC 2.7.10.2 (WEE1 protein, human)
EC 2.7.10.1 (AATK protein, human)
0 (Apoptosis Regulatory Proteins)
تواريخ الأحداث: Date Created: 20220728 Date Completed: 20221222 Latest Revision: 20231213
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9750878
DOI: 10.1038/s41417-022-00513-x
PMID: 35902728
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-5500
DOI:10.1038/s41417-022-00513-x