دورية أكاديمية
The PTEN and ATM axis controls the G1/S cell cycle checkpoint and tumorigenesis in HER2-positive breast cancer
| العنوان: | The PTEN and ATM axis controls the G1/S cell cycle checkpoint and tumorigenesis in HER2-positive breast cancer |
|---|---|
| المؤلفون: | Bassi, Christian, Fortin, Jerome, Snow, Bryan E., Wakeham, Andrew, Ho, Jason, Haight, Jillian, You-Ten, Annick, Cianci, Emily, Buckler, Luke, Gorrini, Chiara, Stambolic, Vuk, Mak, Tak W. |
| المصدر: | Cell Death & Differentiation ; volume 28, issue 11, page 3036-3051 ; ISSN 1350-9047 1476-5403 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cell Biology, Molecular Biology |
| الوصف: | The tumor suppressor PTEN is disrupted in a large proportion of cancers, including in HER2-positive breast cancer, where its loss is associated with resistance to therapy. Upon genotoxic stress, ataxia telangiectasia mutated (ATM) is activated and phosphorylates PTEN on residue 398. To elucidate the physiological role of this molecular event, we generated and analyzed knock-in mice expressing a mutant form of PTEN that cannot be phosphorylated by ATM (PTEN-398A). This mutation accelerated tumorigenesis in a model of HER2-positive breast cancer. Mammary tumors in bi-transgenic mice carrying MMTV-neu and Pten 398A were characterized by DNA damage accumulation but reduced apoptosis. Mechanistically, phosphorylation of PTEN at position 398 is essential for the proper activation of the S phase checkpoint controlled by the PI3K–p27 Kip1 –CDK2 axis. Moreover, we linked these defects to the impaired ability of the PTEN-398A protein to relocalize to the plasma membrane in response to genotoxic stress. Altogether, our results uncover a novel role for ATM-dependent PTEN phosphorylation in the control of genomic stability, cell cycle progression, and tumorigenesis. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41418-021-00799-8 |
| الإتاحة: | https://doi.org/10.1038/s41418-021-00799-8Test https://www.nature.com/articles/s41418-021-00799-8.pdfTest https://www.nature.com/articles/s41418-021-00799-8Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.2CE51585 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41418-021-00799-8 |
|---|