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Control of Glucocorticoid Receptor Levels by PTEN Establishes a Failsafe Mechanism for Tumor Suppression.

Abstract：

: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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Yip HYK,Chee A,Ang CS,Shin SY,Ooms LM,Mohammadi Z,Phillips WA,Daly RJ,Cole TJ,Bronson RT,Nguyen LK,Tiganis T,Hobbs RM,McLean CA,Mitchell CA,Papa A

doi

10.1016/j.molcel.2020.09.027

subject

Has Abstract

pub_date

2020-10-15 00:00:00

pages

279-295.e8

issue

2

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(20)30657-2

journal_volume

80

pub_type

杂志文章

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