Dataset Information

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation.

ABSTRACT: Cyclic AMP (cAMP) signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. Here, we present a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncover a nuclear cAMP microdomain that activates a tumor-suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induces a LATS-dependent pathway leading to phosphorylation of nuclear YAP solely at serine 397 and export of YAP from the nucleus with no change in YAP protein stability. Thus, nuclear cAMP inhibition of nuclear YAP is distinct from other known mechanisms of Hippo regulation. Pharmacologic targeting of specific cAMP microdomains remains an untapped therapeutic approach for cancer; thus, drugs directed at the nuclear cAMP microdomain may provide avenues for the treatment of cancer.

SUBMITTER: Drozdz MM

PROVIDER: S-EPMC9549417 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation.

Drozdz Marek M MM Doane Ashley S AS Alkallas Rached R Desman Garrett G Bareja Rohan R Reilly Michael M Bang Jakyung J Yusupova Maftuna M You Jaewon J Eraslan Zuhal Z Wang Jenny Z JZ Verma Akanksha A Aguirre Kelsey K Kane Elsbeth E Watson Ian R IR Elemento Olivier O Piskounova Elena E Merghoub Taha T Zippin Jonathan H JH

Cell reports 20220901 13

Cyclic AMP (cAMP) signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. Here, we present a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncover a nuclear cAMP microdomain that activates a tumor-suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induce ...[more]

PMID: 36170819

Similar Datasets

Project description:ObjectiveGastric cancer (GC), a malignant tumor of the gastric mucosa, is the second leading cause of cancer deaths worldwide. Although the incidence and mortality of gastric cancer have been reduced in the US and elsewhere, it is still a major public health concern. In this study, we attempted to investigate the function of tripartite motif-containing protein 37 (TRIM37) in GC cell lines in order to propose a new therapy for GC.MethodsThe expression of TRIM37 in GC patients and cell lines was detected by immunohistochemistry, real-time PCR and Western blotting analysis. After TRIM37 knockdown or overexpression, the cell cycle, proliferation and apoptosis, as well as the expression of related proteins, were detected. In addition, in vivo experiments on nude mice were performed.ResultsWe found that TRIM37 expression was significantly elevated in tumor tissues of GC patients and GC cell lines, and patients with high expression of TRIM37 had a poor prognosis. Knockdown of TRIM37 in GC cells significantly inhibited cell proliferation and cell cycle progression, promoted apoptosis, increased cleaved caspase 3 and decreased c-myc and phosphorylation of protein kinase 1/2 (p-ERK1/2). Effects of TRIM37 overexpression were opposite to that of TRIM37 knockdown and were potently attenuated by an ERK1/2 inhibitor. In addition, an ERK1/2 agonist increased TRIM37 and p-ERK1/2 in a dose-dependent manner, and TRIM37 knockdown potently attenuated EGF-induced cell proliferation and expression of TRIM37 and p-ERK1/2. Interestingly, we found that TRIM37 overexpression did not affect the mRNA level of dual-specificity phosphatase 6 (DUSP6), but reduced its protein level in GC cells. Co-immunoprecipitation (Co-IP) analyses revealed that TRIM37 interacted with DUSP6, and TRIM37 overexpression enhanced DUSP6 ubiquitination in GC cells. In vivo experiments on nude mice showed the inhibitory effect of TRIM37 knockdown on tumor growth.ConclusionThese findings suggest that TRIM37 may act as an oncogene in the growth of GC cells and illustrate its potential function as a target in the treatment of GC.

Dataset Information

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation.

Publications

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets