YAP-mediated induction of monoacylglycerol lipase restrains oncogenic transformation
1Laboratory of Molecular Signaling, Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, CA 90095, United States.
Abstract:
The Hippo pathway is an evolutionarily conserved regulator of normal and oncogenic growth. Engagement of Hippo pathway signaling results in the inactivation of the transcriptional coactivator YAP by preventing its nuclear entry. The mechanisms underlying the oncogenic properties of YAP remain incompletely understood. Here we find that although the transactivation (TA) domain of YAP mediates YAP-dependent gene expression, it serves as an inhibitor of YAP-mediated anchorage-independent growth. We identify monoacylglycerol lipase (MAGL) as a YAP transcriptional target and an inhibitor of anchorage-dependent cell growth. Significantly, knockdown of MAGL expression leads to the augmentation of YAP-dependent cell transformation. Our results identify MAGL as a transcriptional target of YAP that restrains YAP-mediated cellular transformation.
Insights
The Hippo pathway regulates growth, with YAP acting as a key coactivator. Researchers found monoacylglycerol lipase (MAGL) restrains YAP-mediated cell transformation, identifying it as a YAP target.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The Hippo pathway is a critical regulator of cell proliferation and organ size.
- YAP (Yes-associated protein) is a transcriptional coactivator and a key downstream effector of the Hippo pathway.
- Aberrant YAP activity is implicated in various cancers, but the precise mechanisms of its oncogenic functions are not fully elucidated.
Purpose of the Study:
- To investigate the mechanisms underlying the oncogenic properties of YAP.
- To identify novel YAP transcriptional targets that modulate YAP-mediated cell growth and transformation.
- To understand the role of YAP's transactivation domain in regulating YAP function.
Main Methods:
- Analysis of YAP's transactivation (TA) domain function in YAP-mediated gene expression and anchorage-independent growth.
- Identification of YAP transcriptional targets using molecular biology techniques.
- Functional studies involving knockdown of identified targets to assess their impact on YAP-dependent cell transformation.
Main Results:
- YAP's TA domain mediates gene expression but inhibits anchorage-independent growth.
- Monoacylglycerol lipase (MAGL) was identified as a direct transcriptional target of YAP.
- MAGL acts as an inhibitor of anchorage-dependent cell growth, and its knockdown enhances YAP-dependent cell transformation.
Conclusions:
- MAGL is a novel transcriptional target of YAP that functions to restrain YAP-mediated cellular transformation.
- The findings reveal a new regulatory mechanism where YAP can induce a target gene (MAGL) that limits its own oncogenic potential.
- Understanding this MAGL-YAP axis may offer new therapeutic strategies for YAP-driven cancers.
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