| Autor: |
Man, Albert K., Young, Lawrence J.T., Tynan, John A., Lesperance, Jacqueline, Egeblad, Mikala, Werb, Zena, Hauser, Craig A., Muller, William J., Cardiff, Robert D., Oshima, Robert G. |
| Předmět: |
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| Zdroj: |
Molecular & Cellular Biology; Dec2003, Vol. 23 Issue 23, p8614-8625, 12p, 12 Color Photographs, 8 Black and White Photographs, 1 Diagram, 4 Charts, 18 Graphs |
| Abstrakt: |
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[sup A72]), to investigate the importance of MAP kinase activation of Ets2 in embryo and tumor development. Ets2[sup A72/A72] mice are viable and develop normally. However, combining the Ets2[sup A72] allele with a deletion mutant of Ets2 results in lethality at E11.5 and shows that Ets2[sup 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[sup A72/A72] females. The Ets2[sup A72/A72] restriction on Neu; VEGF-25 tumor growth was associated with increased p21[sup 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[sup 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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