NF-kappaB-Mediated Repression of GADD153/CHOP: A Role in Breast Cancer Initiation
Abstract
Cells exposed to stresses such as nutrient deprivation, bypoxia, ultraviolet light and environmental toxicants that damage DNA or disrupt endoplasmic reticulum function show induced expression of GADDl53/CHOP, a pro-apoptotic C/EBP family transcription factor. Interestingly, cellular stress also induces the activity of the transcription factor NF-kB, which promotes cell survival by inducing transcription of anti-apoptotic proteins, such as Bcl-2, Bcl-XL, x-TAP, and c-IAP-2. GADDl53 mRNA expression was previously shown in this laboratory to be inhibited by the p65 transactivating subunit of NF-kB. Therefore, cell expressing constitutively active NF-kB, as is the case in 30% of breast cancers, may be predisposed to transformation following cellular stress due to p65-mediated inhibition of GADDl53 expression. To address this possibility, we have generated immortalized mammary epithelial cell line MCF-lOA overexperssing p65. p65 overexpressing cells showed hallmarks of epithelial to mesenchymal transition (ENT) including reduced expression of E-cadherin and Occludin and increased expression of Vimentin. Although the role of EMT in breast cancer initiation is not known, it is essential for invasive growth and motility of breast cancer cells. We also observed that the environmental toxicant methyl methanesulfonate (MMD) induces the expression of the transcription repressor Snail, which has been implicated in EMT. Furthermore, in transient transfection assay, we observed Snail-mediated repression of GADDl53 expression. Interestingly. Sequences with in the first exon of GADDl53 in involve din repression by both NF-kB and Snail. Because Snail expression in Drosophila is regulated by NF-kB homologue dorsal, we propose that NF-kB similarly regulates expression of Snail family transcription repressors, which intern promotes breast cancer progression through enhanced EMT.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2003
- Accession Number
- ADA420151
Entities
People
- Harikrishna Nakshatri