Steroid Receptor Coactivator-3 and Activator Protein-1 Coordinately Regulate the Transcription of Components of the Insulin-like Growth Factor/Akt Signaling Pathway.
From: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Cancer research
- Publish Date: Nov 2006
- ISSN: 0008-5472
- Volume: 66
- Issue: 22
- Pages: 11039-46
- Medium: Print
- Language: English
- Citation (JAMA): Yan Jun, Yu Cheng-Tai, Ozen Mustafa, et al. Steroid Receptor Coactivator-3 and Activator Protein-1 Coordinately Regulate the Transcription of Components of the Insulin-like Growth Factor/Akt Signaling Pathway.. Cancer Res. Nov 2006;66:11039-46
Abstract
Steroid receptor coactivator (SRC)-3, also called amplified in breast cancer 1, is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of target genes. SRC-3 is frequently amplified and/or overexpressed in hormone-sensitive and hormone-insensitive tumors. We reported previously that SRC-3 stimulated prostate cell growth in a hormone-independent manner through activation of AKT signaling pathway. However, the underlying mechanism remains undefined. Here, we exploited the mifepristone-induced SRC-3 LNCaP prostate cancer cell line generated in our laboratory to identify SRC-3-regulated genes by oligonucleotide microarray analysis. We found that SRC-3 up-regulates the expression of multiple genes in the insulin-like growth factor (IGF)/AKT signaling pathway that are involved in cell proliferation and survival. In contrast, knockdown of SRC-3 in PC3 (androgen receptor negative) prostate cancer cells and MCF-7 breast cancer cells reduces their expression. Similarly, in prostate glands of SRC-3 null mice, expressions of these components in the IGF/AKT signal pathway are also reduced. Chromatin immunoprecipitation assay revealed that SRC-3 was directly recruited to the promoters of these genes, indicating that they are direct targets of SRC-3. Interestingly, we showed that recruitment of SRC-3 to two target promoters, IRS-2 and IGF-I, requires transcription factor activator protein-1 (AP-1). Taken together, our results clearly show that SRC-3 and AP-1 can coordinately regulate the transcription of multiple components in the IGF/AKT pathway to ensure ligand-independent cell proliferation and survival of cancer cells.
Mesh Headings (Keywords): Animals, Histone Acetyltransferases, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphoproteins, Promoter Regions (Genetics), Prostatic Neoplasms, Proto-Oncogene Proteins c-akt, Signal Transduction, Somatomedins, Trans-Activators, Transcription Factor AP-1, Transcription, Genetic, Transfection, Up-Regulation
Check for Full Text / PubMed Unique Identifier (PMID): 17108143
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