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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
Published on: September 13, 2018
The LATS2/KPM tumor suppressor is a negative regulator of the androgen receptor
Mark Powzaniuk1, Sheila McElwee-Witmer, Robert L Vogel
1Department of Molecular Endocrinology, Merck Research Laboratories, West Point, Pennsylvania 19486-0004, USA.
Abstract:
The androgen receptor (AR) is a member of the steroid receptor superfamily that plays critical roles in the development and maintenance of the male reproductive system and in prostate cancer. Actions of AR are controlled by interaction with several classes of coregulators. In this study, we have identified LATS2/KPM as a novel AR-interacting protein. Human LATS1 and LATS2 are tumor suppressors that are homologs of Drosophila warts/lats. The interaction surface of LATS2 is mapped to the central region of the protein, whereas the AR ligand binding domain is sufficient for this interaction. LATS2 functions as a modulator of AR by inhibiting androgen-regulated gene expression. The mechanism of LATS2-mediated repression of AR activity appears to involve the inhibition of AR NH2- and COOH-terminal interaction. Chromatin immunoprecipitation assays in human prostate carcinoma cells reveal that LATS2 and AR are present in the protein complex that binds at the promoter and enhancer regions of prostate-specific antigen, and overexpression of LATS2 results in a reduction in androgen-induced expression of endogenous prostate-specific antigen mRNA. Immunohistochemistry shows that LATS2 and AR are localized within the prostate epithelium and that LATS2 expression is lower in human prostate tumor samples than in normal prostate. The results suggest that LATS2 may play a role in AR-mediated transcription and contribute to the development of prostate cancer.
Insights
The study identifies LATS2 as a novel androgen receptor (AR) interacting protein that inhibits AR-regulated gene expression. Lower LATS2 expression in prostate tumors suggests its role in prostate cancer development.
Area of Science:
- Molecular Biology
- Cancer Biology
- Endocrinology
Background:
- The androgen receptor (AR) is crucial for male reproductive system development and prostate cancer.
- AR activity is regulated by interactions with various coregulator proteins.
Purpose of the Study:
- To identify novel AR-interacting proteins.
- To investigate the role of LATS2 in modulating AR activity and its potential involvement in prostate cancer.
Main Methods:
- Protein-protein interaction studies to identify LATS2 as an AR-interacting protein.
- Functional assays to assess LATS2's effect on AR-mediated gene expression.
- Chromatin immunoprecipitation and immunohistochemistry in prostate cancer cells and tissues.
Main Results:
- LATS2 directly interacts with the AR ligand-binding domain.
- LATS2 inhibits androgen-regulated gene expression, including prostate-specific antigen (PSA).
- LATS2 expression is reduced in human prostate tumors compared to normal tissue.
Conclusions:
- LATS2 acts as a novel AR modulator, inhibiting AR transcriptional activity.
- Reduced LATS2 expression may contribute to prostate cancer development by affecting AR signaling.
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