MST1 is a multifunctional caspase-independent inhibitor of androgenic signaling

Date
2011
Authors
Cinar, B.
Collak F.K.
Lopez, D.
Akgul, S.
Mukhopadhyay, N.K.
Kilicarslan, M.
Gioeli, D.G.
Freeman, M.R.
Advisor
Supervisor
Co-Advisor
Co-Supervisor
Instructor
Source Title
Cancer Research
Print ISSN
0008-5472
Electronic ISSN
Publisher
Volume
71
Issue
12
Pages
4303 - 4313
Language
English
Type
Article
Journal Title
Journal ISSN
Volume Title
Series
Abstract

The MST1 serine - threonine kinase, a component of the RASSF1-LATS tumor suppressor network, is involved in cell proliferation and apoptosis and has been implicated in cancer. However, the physiologic role of MST1 in prostate cancer (PCa) is not well understood. Here, we investigated the possibility of a biochemical and functional link between androgen receptor (AR) and MST1 signaling. We showed that MST1 forms a protein complex with AR and antagonizes AR transcriptional activity as shown by coimmunoprecipitation (co-IP), promoter reporter analysis, and molecular genetic methods. In vitro kinase and site-specific mutagenesis approaches indicate that MST1 is a potent AR kinase; however, the kinase activity of MST1 and its proapoptotic functions were shown not to be involved in inhibition of AR. MST1 was also found in AR - chromatin complexes, and enforced expression of MST1 reduced the binding of AR to a well-characterized, androgen-responsive region within the prostate-specific antigen promoter. MST1 suppressed PCa cell growth in vitro and tumor growth in mice. Because MST1 is also involved in regulating the AKT1 pathway, this kinase may be an important new link between androgenic and growth factor signaling and a novel therapeutic target in PCa. ©2011 AACR.

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Keywords
androgen receptor, prostate specific antigen, protein MST1, protein serine threonine kinase, unclassified drug, animal cell, animal experiment, animal model, article, cancer inhibition, controlled study, enzyme activity, growth inhibition, hormone binding, hormone inhibition, hormone protein complex, immunoprecipitation, in vitro study, in vivo study, male, molecular genetics, mouse, nonhuman, priority journal, promoter region, prostate cancer, signal transduction, site directed mutagenesis, transcription initiation, Androgen Receptor Antagonists, Animals, Caspases, Cercopithecus aethiops, Chromatin, COS Cells, HEK293 Cells, Humans, Male, Mice, Phosphorylation, Prostatic Neoplasms, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Receptors, Androgen, Signal Transduction
Citation
Published Version (Please cite this version)