Journal article
v-Ha-RaS oncogene upregulates the 92-kDa type IV collagenase (MMP-9) gene by increasing cellular superoxide production and activating NF-κB
Free radical biology & medicine, Vol.31(4), pp.520-529
2001
DOI: 10.1016/S0891-5849(01)00613-X
PMID: 11498285
Abstract
Matrix metalloproteinase 9 (MMP-9) degrades basement membrane type IV collagen and is expressed during cellular migration and invasion. Here we show that v-Ha-Ras overexpression in rat kidney epithelial cells (REC) caused upregulation of MMP-9 gene expression in part by increasing cellular oxidant levels. v-Ha-Ras mediated the production of superoxide in Ras-transfected cells, which was associated with upregulated MMP-9 gene expression. Conversely, v-Ha-Ras expression decreased steady-state levels of mRNAs from tissue inhibitor of metalloproteinase 1 (TIMP-1), an inhibitor of MMP-9; plasminogen activator inhibitor 1 (PAI-1), which indirectly activates MMP-9 by increasing plasmin levels; and collagen IV, a substrate of MMP-9 and a major component of basement membrane. Gel mobility shift assays demonstrated that Ras overexpression enhanced NF-κB, but not AP-1 DNA binding to motifs in the MMP-9 gene promoter. The Ras-induced increase in NF-κB DNA binding could be inhibited by treatment with the antioxidants N-acetyl-L-cysteine and glutathione monoester, suggesting that intracellular oxidant levels can mediate MMP-9 transcription. Our findings identify an important role for Ras in the regulation of MMP-9 expression, and suggest that increased superoxide production can upregulate MMP-9 expression and thus contribute to malignant conversion.
Details
- Title: Subtitle
- v-Ha-RaS oncogene upregulates the 92-kDa type IV collagenase (MMP-9) gene by increasing cellular superoxide production and activating NF-κB
- Creators
- Ji-Qin Yang - Free Radical and Radiation Biology Program and Holden Comprehensive Cancer Center Department of Radiology, The University of Iowa, Iowa City, IA, USAWeiling Zhao - Free Radical and Radiation Biology Program and Holden Comprehensive Cancer Center Department of Radiology, The University of Iowa, Iowa City, IA, USAHong Duan - Free Radical and Radiation Biology Program and Holden Comprehensive Cancer Center Department of Radiology, The University of Iowa, Iowa City, IA, USAMike E.C Robbins - Free Radical and Radiation Biology Program and Holden Comprehensive Cancer Center Department of Radiology, The University of Iowa, Iowa City, IA, USAGarry Buettner - Free Radical and Radiation Biology Program and Holden Comprehensive Cancer Center Department of Radiology, The University of Iowa, Iowa City, IA, USALarry W Oberley - Free Radical and Radiation Biology Program and Holden Comprehensive Cancer Center Department of Radiology, The University of Iowa, Iowa City, IA, USAFrederick E Domann - Free Radical and Radiation Biology Program and Holden Comprehensive Cancer Center Department of Radiology, The University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Free radical biology & medicine, Vol.31(4), pp.520-529
- DOI
- 10.1016/S0891-5849(01)00613-X
- PMID
- 11498285
- NLM abbreviation
- Free Radic Biol Med
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 2001
- Academic Unit
- Pathology; Surgery; Radiation Oncology
- Record Identifier
- 9984046927502771
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