Cytoplasmic, full length and novel cleaved variant, TBLR1 reduces apoptosis in prostate cancer under androgen deprivation
| Autor: | Xuelin Zhong, Robert J. Schneider, Xinyu Wu, Ross S. Basch, Ling Hang Wang, Thomas A. Neubert, Laurey Steinke, Larion Santiago, Ying Shen, Jack Y. Zhang, David E. Levy, Garrett Daniels, Feng-Xia Liang, Xin Li, Peng Lee, Xinmin Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Cytoplasm DNA Mutational Analysis Active Transport Cell Nucleus Receptors Cytoplasmic and Nuclear Apoptosis castration resistance Androgen deprivation therapy 03 medical and health sciences 0302 clinical medicine Protein Domains Cell Movement Cell Line Tumor subcellular localization medicine Humans Neoplasm Invasiveness Nuclear protein Nuclear export signal Cellular localization Cell Proliferation Cell Nucleus business.industry Nuclear Proteins Prostatic Neoplasms Subcellular localization prostate cancer 3. Good health Cell biology Androgen receptor Repressor Proteins Cell nucleus 030104 developmental biology medicine.anatomical_structure HEK293 Cells Oncology Nuclear receptor cvTBLR1 Drug Resistance Neoplasm Receptors Androgen 030220 oncology & carcinogenesis Immunology Androgens Mutagenesis Site-Directed TBLR1 business Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | TBLR1/TBL1XR1, a core component of the nuclear receptor corepressor (NCoR) complex critical for the regulation of multiple nuclear receptors, is a transcriptional coactivator of androgen receptor (AR) and functions as a tumor suppressor when expressed in the nucleus in prostate. Subcellular localization of a protein is critical for its function, and although TBLR1, as a transcriptional cofactor, has been primarily viewed as a nuclear protein, many cells also express variable levels of cytoplasmic TBLR1 and its cytoplasmic specific functions have not been studied. Prostate cancer (PCa) cells express moderately higher level of cytoplasmic TBLR1 compared to benign prostate cells. When comparing androgen-dependent (AD) to androgen-independent (AI) PCa, AI cells contain very high levels of TBLR1 cytoplasmic expression and low levels of nuclear expression. Overexpression of cytoplasmic TBLR1 in AD cells inhibits apoptosis induced by androgen deprivation therapy, either in an androgen free condition or in the presence of bicalutamide. Additionally, we identified a cytoplasmic specific isoform of TBLR1 (cvTBLR1) approximately 5 kDa lower in molecular weight, that is expressed at higher levels in AI PCa cells. By immunoprecipitation, we purified cvTBLR1 and using mass spectrometry analysis combined with N-terminal TMPP labeling and Edman degradation, we identified the cleavage site of cvTBLR1 at amino acid 89, truncating the first 88 amino acids of the N-terminus of the full length protein. Functionally, cvTBLR1 expressed in the cytoplasm reduced apoptosis in PCa cells and promoted growth, migration, and invasion. Finally, we identified a nuclear export signal sequence for TBLR1 cellular localization by deletion and site-directed mutagenesis. The roles of TBLR1 and cvTBLR1 provide novel insights into the mechanism of castration resistance and new strategies for PCa therapy. |
| Databáze: | OpenAIRE |
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