Journal article
Down Regulation of CSL Activity Inhibits Cell Proliferation in Prostate and Breast Cancer Cells
Journal of cellular biochemistry, Vol.112(9), pp.2340-2351
09/01/2011
DOI: 10.1002/jcb.23157
PMID: 21520243
Abstract
The Notch receptor pathway provides a paradigm for juxtacrine signaling pathways and controls stem cell function, developmental cell fate decisions, and cellular differentiation. The Notch pathway is constitutively activated in human cancers by chromosomal rearrangements, activating point mutations, or altered expression patterns. Therefore, the Notch pathway is the subject of chemotherapeutic intervention in a variety of human cancers. Notch receptor activation results in the gamma-secretase dependent proteolytic cleavage of the receptor to liberate the Notch intracellular domain that acts to mediate co-activator recruitment to the DNA binding transcription factor, CSL (CBF-1/RBP-Jk, Su(H), Lag-1). Therapeutic targeting of the Notch pathway by gamma-secretase inhibitors prevents NICD production and regulates CSL-dependent transcriptional activity. To interrogate the loss of CSL activity in breast and prostate cancer cells, we used lentiviral-based shRNA knockdown of CSL. Knockdown of CSL expression was assessed by decreased DNA binding activity and resulted in decreased cell proliferation. In contrast, gamma-secretase inhibitor (GSI) treatment of these prostate and breast cancer cell lines resulted in minimal growth effects. PCR profiling of Notch pathway genes identified expression changes in few genes (Delta-like-1, Deltex-1, LM02, and SH2D1A) after CSL knockdown. Consistent with differential effects of GSI on cell survival, GSI treatment failed to recapitulate the gene expression changes observed after CSL knockdown. Thus, CSL inhibition may provide a more effective mechanism to inhibit Notch-pathway dependent cancer cell proliferation as compared to GSI treatment. J. Cell. Biochem. 112: 2340-2351, 2011. (C) 2011 Wiley-Liss, Inc.
Details
- Title: Subtitle
- Down Regulation of CSL Activity Inhibits Cell Proliferation in Prostate and Breast Cancer Cells
- Creators
- Thomas Yong - Louisiana State University Health Sciences Center ShreveportAmanda Sun - Louisiana State University Health Sciences Center ShreveportMichael D. Henry - Roy J. and Lucille A. Carver College of MedicineShari Meyers - Louisiana State University Health Sciences Center ShreveportJ. Nathan Davis - Louisiana State University Health Sciences Center Shreveport
- Resource Type
- Journal article
- Publication Details
- Journal of cellular biochemistry, Vol.112(9), pp.2340-2351
- Publisher
- Wiley
- DOI
- 10.1002/jcb.23157
- PMID
- 21520243
- ISSN
- 0730-2312
- eISSN
- 1097-4644
- Number of pages
- 12
- Grant note
- Feist-Weiller Cancer Center (LSUHSC-Shreveport)
- Language
- English
- Date published
- 09/01/2011
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Radiation Oncology
- Record Identifier
- 9984303003602771
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