期刊
HUMAN MUTATION
卷 31, 期 1, 页码 74-80出版社
WILEY
DOI: 10.1002/humu.21138
关键词
androgen receptor; AR; prostate cancer; PCa; aberrant splicing; 22Rv1; truncated receptor
资金
- Alsace Centre le Cancer (ATGC)
- Ligue Nationale Centre le Cancer - Comites du Bas-Rhin et du Haut-Rhin
- Association pour la Recherche sur les Tumeurs de la Prostate
- Association pour la Recherche Contre le Cancer [1022]
Advanced prostate cancer (PCa) has emerged as a public health concern due to population aging. Although androgen deprivation has proven efficacy in this condition, most advanced PCa patients will have to face failure of androgen deprivation as a treatment. Mutations in the androgen receptor (AR) from tumor cells have been shown to induce androgen independency both in PCa cell lines and in the clinic. We have investigated the molecular events leading to androgen independency in the 22Rv1 cell line, a commonly used preclinical model of PCa. Besides AR mutants that have been described so far, including nonsense mutations, recent data have focused on AR pre-mRNA aberrant splicing as a new mechanism leading to constitutively active truncated AR variants. In this article, we describe two novel variants arising from aberrant splicing of AR pre MRNA, characterized by long mRNA transcripts that encode truncated, constitutively active proteins. We also describe several new nonsense mutants that share ligand independency and transcriptional activity. Finally, we show that alongside these mutants, 22Rv1 cells also express a mutant AR lacking exon 3 tandem duplication, a major feature of this cell line. By describing unreported AR mutants in the 22Rv1 cell line, our data emphasize the complexity and heterogeneity of molecular events that occur in preclinical models, and supposedly in the clinic. Future work on the 22Rv1 cell line should take into account the concomitant expression of various AR mutants. Hum Mutat 31:74-80, 2010. (C) 2009 Wiley-Liss, Inc.
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