期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 41, 页码 21541-21552出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.730960
关键词
breast cancer; cell signaling; hypoxia; hypoxia-inducible factor (HIF); tumor suppressor gene
资金
- National Institutes of Health [R03 CA12582]
- Florida Department of Health
- Violet Brownhill Trust
- Scientific and Technological Research Council of Turkey (TUBITAK)
Reduced ATM function has been linked to breast cancer risk, and the TRIM29 protein is an emerging breast cancer tumor suppressor. Here we show that, in cultured breast tumor and non-tumorigenic mammary epithelial cells, TRIM29 is up-regulated in response to hypoxic stress but not DNA damage. Hypoxia-induced up-regulation of TRIM29 is dependent upon ATM and HIF1 and occurs through increased transcription of the TRIM29 gene. Basal expression of TRIM29 is also down-regulated in cells expressing diminished levels of ATM, and findings suggest that this occurs through basal NF-B activity as knockdown of the NF-B subunit RelA suppresses TRIM29 abundance. We have previously shown that the activity of the TWIST1 oncogene is antagonized by TRIM29 and now show that TRIM29 is necessary to block the up-regulation of TWIST1 that occurs in response to hypoxic stress. This study establishes TRIM29 as a hypoxia-induced tumor suppressor gene and provides a novel molecular mechanism for ATM-dependent breast cancer suppression.
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