| Ets family transcription factors are regulated by signal transduction pathways. Phosphorylation of the Ets-1 and Ets-2 at a single conserved threonine residue (T38 and T72, respectively) by ras-MAPK pathways leads to their activation and persistent target genes expression. The phosphorylation of Ets-2 affected its activity, as well as its protein partnership. Ets-2 interacted with Brg-1 or BS69 co-repressors in a phosphorylation dependent manner, and repressed target gene expression.; Ets-2 knockout mice are embryonic lethal due to an extra-embryonic defect, whereas ets-2T72A/T72A mice are viable and fertile, with no obvious abnormality. Ets-2 is constitutively phosphorylated in macrophages derived from motheaten-viable (mev) mice, while its phosphorylation is tightly regulated in wt cells. The aberrant Ets-2 phosphorylation correlated with increased target gene expression and cell survival. To directly test the role of Ets-2 phosphorylation in inflammation, the ets-2T72A allele was introduced into mev mice. In contrast to ets2+/+, mev/mev mice, ets-2T72A/T72A, mev/mev mice were fertile, had increased life span and body weight, elevated macrophage apoptosis in the absence of CSF-1, but reduced inflammation and expression of inflammatory genes, including cytokines (TNFα), chemokines (MIP1α, β), extracellular matrix proteases (MMP9), cell adhesion molecule (integrin αM) in lungs and macrophages.; Both ets-1−/− mice and Ets-2T72A/T72A mice are viable and fertile. To reveal Ets-2 function possibly masked by gene redundancy, we mated ets-2T72A/T72A mice with Ets-1 knockout mice. Ets-1−/−, Ets-2T72A/T72A mice died between embryonic day 11.5 to 14.5, with dramatic angiogenesis and cardiovascular defects. Compared to control embryos, the double mutant embryos expressed lower levels of Ets target genes, such as Ang1, Tie2, MMP3, MMP9, and Fli-1, but elevated levels of VEGF.; Therefore, Ets-2 phosphorylation is important in immune response, angiogenesis and cancer. To further explore the in vivo function of Ets-2, an ets-2 conditional knockout allele was developed. This allele is useful to address the cell antonymous function of Ets-2 in inflammation, angiogenesis and tumorgenesis (in tumor cells or stromal cells, including fibroblasts, macrophages and vessel cells) and other human diseases. Understanding how Ets-2 works these diseases may have important clinical implications, both for early diagnosis and developing of novel, effective therapy methods. |
