Based on our recent findings on androgen receptor (AR) phosphorylation at serine 81 and AR interactions with protein phosphatase 1 (PP1), we are updating Aims 4 and 5 (ROO phase) fronri the parental grant. These two Aims will be integrated into Aim 5 of the updated proposal for the ROO phase, and a new Aim 4 will build on our recent findings made during the K99 phase examining AR serine 81 phosphorylation and AR association with chromatin.
Aim 4. Characterize the higher molecular weight AR molecules that associate with AR chromatin binding and serine 81 phosphorylation. Our data suggest that serine 81 phosphorylation may target AR for further posttranslational modifications (such as monoubiquitylation or SUMO conjugation) that may be required for stable chromatin binding and transcriptional activation. Biochemical and molecular approaches will be used to test these hypotheses.
Aim 5. Determine the functional importance of AR phosphorylation/ dephosphorylation and its interaction with PPip. Our initial Aims 4 and 5 proposed to study the interactions between AR and PP1. The PP1 catalytic subunit has 3 isoforms, a, p, and y, and our recent data indicate that PP1P has the greatest interaction. Therefore, the experiments have been modified to focus on regulation of AR functions by PPip.

Public Health Relevance

The androgen receptor plays a critical role in prostate cancer development and progression. These studies will provide new insights into how androgen receptor functions are regulated and lead to approaches for modulating or blocking androgen receptor activities in prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
4R00CA135592-03
Application #
8211876
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2011-02-01
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
3
Fiscal Year
2011
Total Cost
$241,529
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Liu, Xiaming; Han, Weiwei; Gulla, Sarah et al. (2016) Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation. Oncotarget 7:1754-64
Liu, Xiaming; Han, Weiwei; Gulla, Sarah et al. (2016) Androgen ablation elicits PP1-dependence for AR stabilization and transactivation in prostate cancer. Prostate 76:649-61
Gao, Shuai; Gao, Yanfei; He, Housheng Hansen et al. (2016) Androgen Receptor Tumor Suppressor Function Is Mediated by Recruitment of Retinoblastoma Protein. Cell Rep 17:966-976
Sowalsky, Adam G; Xia, Zheng; Wang, Liguo et al. (2015) Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer. Mol Cancer Res 13:98-106
Chen, Shaoyong; Gulla, Sarah; Cai, Changmeng et al. (2012) Androgen receptor serine 81 phosphorylation mediates chromatin binding and transcriptional activation. J Biol Chem 287:8571-83
Cai, Changmeng; He, Housheng Hansen; Chen, Sen et al. (2011) Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 20:457-71