Journal article
Novel Insight into KLF4 Proteolytic Regulation in Estrogen Receptor Signaling and Breast Carcinogenesis
The Journal of biological chemistry, Vol.287(17), pp.13584-13597
04/20/2012
DOI: 10.1074/jbc.M112.343566
PMCID: PMC3340146
PMID: 22389506
Abstract
Kruppel-like factor 4 (KLF4), a zinc finger-containing transcriptional factor, is a pivotal regulator of cellular fate. KLF4 has attracted considerable attention for its opposing effect in carcinogenesis as tumor suppressor (e. g. colorectal cancer) or oncoprotein (e. g. breast cancer), depending on tissue context, with the underlying mechanism remaining largely unknown. Here we report that KLF4 mediates estrogen signaling in breast cancer formation. Accumulation of KLF4 by inhibiting its turnover triggers estrogen-induced transactivation. We identified Von Hippel-Lindau, pVHL, as the protein that governs KLF4 turnover in breast cancer cells and demonstrated that estrogen-induced down-regulation of pVHL facilitates accumulation of KLF4. We provide mechanistic insights into KLF4 steady-state degradation as well as its elevation in the presence of estrogen and show that elevated levels of pVHL or depletion of KLF4 attenuates the estrogen-induced transactivation and cell growth. Finally, immunohistochemical staining revealed reduced concentration of pVHL and accumulation of KLF4 in breast cancer tissues. We thus propose that suppression of pVHL in response to estrogen signaling results in elevation of KLF4, which mediates estrogen-induced mitogenic effect.
Details
- Title: Subtitle
- Novel Insight into KLF4 Proteolytic Regulation in Estrogen Receptor Signaling and Breast Carcinogenesis
- Creators
- Dong Hu - UPMC Hillman Cancer CenterZhuan Zhou - UPMC Hillman Cancer CenterNancy E. Davidson - UPMC Hillman Cancer CenterYi Huang - University of PittsburghYong Wan - UPMC Hillman Cancer Center
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.287(17), pp.13584-13597
- DOI
- 10.1074/jbc.M112.343566
- PMID
- 22389506
- PMCID
- PMC3340146
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 14
- Grant note
- CA115943 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Pittsburgh Woman Cancer Fund R01CA154695 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 04/20/2012
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383313702771
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