期刊
ONCOGENE
卷 33, 期 24, 页码 3140-3150出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.284
关键词
prostate cancer; androgen deprivation therapy; RNA splice variant; alternative splicing
资金
- Pacific Northwest Prostate Cancer SPORE, National Cancer Institute [P50CA097186]
- Prostate Cancer Canada [RS2013-58]
- Canadian Institute of Health Research [MOP-97934]
- Department of Defence plus Veterans Administration Grants
- Prostate Cancer Foundation
- NIH [P01 CA163227]
Prostate tumors develop resistance to androgen deprivation therapy (ADT) by multiple mechanisms, one of which is to express constitutively active androgen receptor (AR) splice variants lacking the ligand-binding domain. AR splice variant 7 (AR-V7, also termed AR3) is the most abundantly expressed variant that drives prostate tumor progression under ADT conditions. However, the molecular mechanism by which AR-V7 is generated remains unclear. In this manuscript, we demonstrated that RNA splicing of AR-V7 in response to ADT was closely associated with AR gene transcription initiation and elongation rates. Enhanced AR gene transcription by ADT provides a prerequisite condition that further increases the interactions between AR pre-mRNA and splicing factors. Under ADT conditions, recruitment of several RNA splicing factors to the 3' splicing site for AR-V7 was increased. We identified two RNA splicing enhancers and their binding proteins (U2AF65 and ASF/SF2) that had critical roles in splicing AR pre-mRNA into AR-V7. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-V7 levels in prostate cancer cells.
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