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 (Ets2A72), to investigate the importance of MAP kinase activation of Ets2 in embryo and tumor development. Ets2A72/A72 mice are viable and develop normally. However, combining the Ets2A72 allele with a deletion mutant of Ets2 results in lethality at E11.5 and shows that Ets2A72 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 Ets2A72/A72 females. The Ets2A72/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 Ets2A72/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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 8614-8625 |
| Number of pages | 12 |
| Journal | Molecular and Cellular Biology |
| Volume | 23 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2003 |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors. / Man, Albert K.; Young, Lawrence J.T.; Tynan, John A.; Lesperance, Jacqueline; Egeblad, Mikala; Werb, Zena; Hauser, Craig A.; Muller, William J.; Cardiff, Robert; Oshima, Robert G.
In: Molecular and Cellular Biology, Vol. 23, No. 23, 01.12.2003, p. 8614-8625.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors
AU - Man, Albert K.
AU - Young, Lawrence J.T.
AU - Tynan, John A.
AU - Lesperance, Jacqueline
AU - Egeblad, Mikala
AU - Werb, Zena
AU - Hauser, Craig A.
AU - Muller, William J.
AU - Cardiff, Robert
AU - Oshima, Robert G.
PY - 2003/12/1
Y1 - 2003/12/1
N2 - 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 (Ets2A72), to investigate the importance of MAP kinase activation of Ets2 in embryo and tumor development. Ets2A72/A72 mice are viable and develop normally. However, combining the Ets2A72 allele with a deletion mutant of Ets2 results in lethality at E11.5 and shows that Ets2A72 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 Ets2A72/A72 females. The Ets2A72/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 Ets2A72/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.
AB - 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 (Ets2A72), to investigate the importance of MAP kinase activation of Ets2 in embryo and tumor development. Ets2A72/A72 mice are viable and develop normally. However, combining the Ets2A72 allele with a deletion mutant of Ets2 results in lethality at E11.5 and shows that Ets2A72 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 Ets2A72/A72 females. The Ets2A72/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 Ets2A72/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.
UR - http://www.scopus.com/inward/record.url?scp=0242468991&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0242468991&partnerID=8YFLogxK
U2 - 10.1128/MCB.23.23.8614-8625.2003
DO - 10.1128/MCB.23.23.8614-8625.2003
M3 - Article
C2 - 14612405
AN - SCOPUS:0242468991
VL - 23
SP - 8614
EP - 8625
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 23
ER -