Role of TMS1 Silencing in the Resistance of Breast Cancer Cells to Apoptosis
Abstract
We identified a gene TMS1 that is subject to epigenetic silencing in breast cancer, although the precise role of TMS1 in the pathogenesis of cancer is unknown. We hypothesize that silencing of TMS1 contributes to breast carcinogenesis by allowing cells to bypass apoptosis, and consequently may cause cells to be resistant to chemotherapy. We created a TMS1 loss-of-function model in MCF7 cells using siRNA, and determined that cells lacking TMS1 expression are approximately 2-fold more resistant to certain apoptotic stimuli. Also, whereas TMS1 is not required for TNFalpha or TRAIL-induced activation of NF-kB or caspase-8, it promotes caspase-8 activation independently of death receptor stimuli. We also find that TMS1 is upregulated by TNFalpha in breast epithelial cells, but not in fibroblasts. This induction was blocked by knockdown of RelA/p65, and is not dependent on new protein synthesis or mRNA stability, suggesting a direct effect on TMS1 transcription. Consistent with this, TNFalpha treatment causes local chromatin alterations at the TMS1 locus. Although previous work has suggested that TMS1 is regulated by p53, we found little impact of DNA damaging agents on TMS1 expression. Upregulation of TMS1 by TNFalpha and subsequent activation of caspase-8 could function to amplify death receptor-induced apoptosis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2005
- Accession Number
- ADA444002
Entities
People
- Melissa J. Parsons
- Paula M. Vertino
Organizations
- Emory University