Man, A. K., Young, L. J. T., Tynan, J. A., Lesperance, J., Egeblad, M., Werb, Z., Hauser, C. A., Muller, W. J., Cardiff, R. D., Oshima, R. G. (2003) Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors. Molecular and Cellular Biology, 23 (23). pp. 8614-8625. ISSN 02707306 (ISSN)
Abstract
The Ets2 transcription factor is regulated by mitogen-activated protein (MAP) kinase phosphorylation of a single threonine residue. We generated by gene targeting a single codon mutation in Ets2 substituting Ala for the critical Thr-72 phosphorylation site (Ets2 A72), to investigate the importance of MAP kinase activation of Ets2 in embryo and tumor development. Ets2 A72/A72 mice are viable and develop normally. However, combining the Ets2 A72 allele with a deletion mutant of Ets2 results in lethality at E11.5 and shows that Ets2 A72 is a hypomorphic allele. Mammary tumors caused by transgenic polyomavirus middle T antigen, activated Neu (Erbb2), or the combination of Neu and transgenic VEGF (Neu; VEGF-25) were all restricted in Ets2 A72/A72 females. The Ets2 A72/A72 restriction on Neu; VEGF-25 tumor growth was associated with increased p21 Cip1 expression. The size of tumors transplanted into fat pads of mice with Ets2 targeted alleles was correlated directly with Ets2 activity and fewer stromal cells expressing matrix metalloproteinase 9 (MMP-9). Decreased MMP-3 and MMP-9 mRNAs were confirmed in Ets2 A72/A72 macrophages. Activation of Ets2 at Thr-72 acts in the stroma, downstream of vascular endothelial growth factor production, in part through the regulation of macrophage proteases to support the progression of Neu- and polyomavirus middle-T-initiated mammary tumors.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | gelatinase B mitogen activated protein kinase protein p21 stromelysin transcription factor Ets 2 vasculotropin virus middle T antigen allele amino acid substitution animal cell animal experiment animal model animal tissue article breast tumor cancer graft carcinogenesis codon controlled study correlation analysis embryo embryo development enzyme activation gene deletion gene mutation gene targeting macrophage mouse nonhuman priority journal protein function protein phosphorylation protein synthesis regulatory mechanism stroma substitution reaction transgenic mouse Alleles Animals Base Sequence Cyclin-Dependent Kinase Inhibitor p21 Cyclins DNA, Complementary DNA-Binding Proteins Embryonic and Fetal Development Female Gene Expression Heterozygote Macrophages Mammary Neoplasms, Experimental Matrix Metalloproteinases Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinases Phenotype Phosphorylation Pregnancy Proto-Oncogene Protein c-ets-2 Proto-Oncogene Proteins Repressor Proteins Trans-Activators Transcription Factors Vascular Endothelial Growth Factor A Animalia Mus musculus Polyomavirus |
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > cancer > cancer types > breast cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p21 diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Egeblad lab |
| Depositing User: | Matt Covey |
| Date: | 2003 |
| Date Deposited: | 14 Mar 2013 19:54 |
| Last Modified: | 14 Mar 2013 19:54 |
| PMCID: | PMC262691 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27805 |
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