BRCA1-IRIS regulates cyclin D1 expression in breast cancer cells.
The regulator of cell cycle progression, cyclin D1, is up-regulated in breast cancer cells; its expression is, in part, dependent on ERalpha signaling. However, many ERalpha-negative tumors and tumor cell lines (e.g., SKBR3) also show over-expression of cyclin D1. This suggests that, in addition to ERalpha signaling, cyclin D1 expression ... is under the control of other signaling pathways; these pathways may even be over-expressed in the ERalpha-negative cells. We previously noticed that both ERalpha-positive and -negative cell lines over-express BRCA1-IRIS mRNA and protein. Furthermore, the level of over-expression of BRCA1-IRIS in ERalpha-negative cell lines even exceeded its over-expression level in ERalpha-positive cell lines. In this study, we show that: (1) BRCA1-IRIS forms complex with two of the nuclear receptor co-activators, namely, SRC1 and SRC3 (AIB1) in an ERalpha-independent manner. (2) BRCA1-IRIS alone, or in connection with co-activators, is recruited to the cyclin D1 promoter through its binding to c-Jun/AP1 complex; this binding activates the cyclin D1 expression. (3) Over-expression of BRCA1-IRIS in breast cells over-activates JNK/c-Jun; this leads to the induction of cyclin D1 expression and cellular proliferation. (4) BRCA1-IRIS activation of JNK/c-Jun/AP1 appears to account for this, because in cells that were depleted from BRCA1-IRIS, JNK remained inactive. However, depletion of SRC1 or SRC3 instead reduced c-Jun expression. Our data suggest that this novel signaling pathway links BRCA1-IRIS to cellular proliferation through c-Jun/AP1 nuclear pathway; finally, this culminates in the increased expression of the cyclin D1 gene.
Mesh Terms:
BRCA1 Protein, Breast Neoplasms, Cell Proliferation, Chromosomal Proteins, Non-Histone, Cyclin D1, Enzyme Activation, Estrogen Receptor alpha, Exons, Gene Silencing, Humans, JNK Mitogen-Activated Protein Kinases, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-myc, Trans-Activators, Transcription Factor AP-1, Transcription, Genetic, Transcriptional Activation, Tumor Cells, Cultured
BRCA1 Protein, Breast Neoplasms, Cell Proliferation, Chromosomal Proteins, Non-Histone, Cyclin D1, Enzyme Activation, Estrogen Receptor alpha, Exons, Gene Silencing, Humans, JNK Mitogen-Activated Protein Kinases, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-myc, Trans-Activators, Transcription Factor AP-1, Transcription, Genetic, Transcriptional Activation, Tumor Cells, Cultured
Exp. Cell Res.
Date: Oct. 01, 2006
PubMed ID: 16860316
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