Control of Glucocorticoid Receptor Levels by PTEN Establishes a Failsafe Mechanism for Tumor Suppression
| Autor: | Annabel Chee, Catriona McLean, Roderick T. Bronson, Christina Anne Mitchell, Ching-Seng Ang, Sung-Young Shin, Lan K. Nguyen, Lisa M Ooms, Zainab Mohammadi, Tony Tiganis, Hon Yan Kelvin Yip, Robin M. Hobbs, Roger J. Daly, Antonella Papa, Tim J Cole, Wayne A. Phillips |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Programmed cell death
Proteome Carcinogenesis Mammary Neoplasms Animal Biology medicine.disease_cause Models Biological Dexamethasone law.invention Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences Receptors Glucocorticoid 0302 clinical medicine Glucocorticoid receptor law Cell Line Tumor medicine Animals Humans PTEN Phosphorylation Receptor Molecular Biology PI3K/AKT/mTOR pathway Cell Proliferation 030304 developmental biology 0303 health sciences Cell Death Protein Stability Cell growth PTEN Phosphohydrolase Cell Biology Isoenzymes Organoids Mutation Cancer research biology.protein Suppressor Female Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery |
| Zdroj: | Molecular Cell. 80:279-295.e8 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2020.09.027 |
| Popis: | The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. While the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Here, using knockin (KI) mice harboring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. Thus, we find that the dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN loss-driven cancers. |
| Databáze: | OpenAIRE |
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