Control of Glucocorticoid Receptor Levels by PTEN Establishes a Failsafe Mechanism for Tumor Suppression.
Animals
Carcinogenesis
Cell Death
Cell Line, Tumor
Cell Proliferation
Dexamethasone
/ pharmacology
Female
Humans
Isoenzymes
/ metabolism
Mammary Neoplasms, Animal
/ metabolism
Mice
Models, Biological
Mutation
/ genetics
Organoids
/ pathology
PTEN Phosphohydrolase
/ genetics
Phosphatidylinositol 3-Kinases
/ genetics
Phosphorylation
Protein Stability
Proteome
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Receptors, Glucocorticoid
/ metabolism
failsafe mechanism
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
15 10 2020
15 10 2020
Historique:
received:
13
11
2019
revised:
03
08
2020
accepted:
22
09
2020
entrez:
16
10
2020
pubmed:
17
10
2020
medline:
30
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33065020
pii: S1097-2765(20)30657-2
doi: 10.1016/j.molcel.2020.09.027
pii:
doi:
Substances chimiques
Isoenzymes
0
Proteome
0
Receptors, Glucocorticoid
0
Dexamethasone
7S5I7G3JQL
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
PTEN Phosphohydrolase
EC 3.1.3.67
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
279-295.e8Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.