Cell Regulation Group - Functional Characteristics of ATF2

The leucine zipper transcription factor ATF2 is a member of the AP-1 family which regulates gene expression in response to a variety of changes in the cellular environment. ATF2 is activated through phosphorylation of two specific threonine residues positioned in the trans-activation domain and is mediated by the stress activated MAP kinases (figure 1) JNK and p38. This implies that some of the diverse biological functions that are known to involve these kinase pathways may be mediated by changes in gene expression controlled by ATF2. To date, few definitive targets of ATF-2 have been identified although it is known that the factor can bind to sites either as a homodimer or as a heterodimer with other AP-1 factors, such as cJun, a well characterised oncogenic product.

 

leucine zipper transcription factor ATF2

Figure 3 - leucine zipper transcription factor ATF2

 

Why Study the Function and Regulation of ATF2?

Many reports, mostly using in vitro systems, have implicated ATF2 in numerous growth and development programs and in response to geno- and cytotoxic stresses. For example, depending upon cellular context, ATF2 has been implicated in the regulation of cell proliferation, e.g. in chondrocytes and in the regulation of apoptosis. Other biological functions for ATF2 include responses to neuronal stresses, as well as a role in inflammatory responses, such as the activation of T-cell specific genes after viral infection. In most of these cases however, the potential role of ATF2 has not been verified in whole animal models.

In order to address the in vivo role of ATF2 and its regulation through phosphorylation, we have generated a number of mutant mice where ATF2 activity is compromised. ATF2 null mice die very soon after birth from severe respiratory distress. In order to circumvent this problem we have generated a mouse containing a floxed ATF2 allele and crossed these mice to strains expressing Cre recombinase in a tissue specific manner. For example, the endothelial cell-specific inactivation of ATF2 (figure 4) results in mice that develop normally in utero but die within weeks after birth expressing defects in the microvasculature of the small intestine. This suggests an important role for ATF2 in a stress response function early in post embryonic life.

 

Tie1-Cre dependent GFP expression in the microvasculature of the small intestine

Figure 4 - Tie1-Cre dependent GFP expression in the microvasculature of the small intestine (green...endothelial cells, red...red blood cells)


Future studies will focus on the phenotypes of these mice and the molecular basis for the defects that are seen. Of particular importance will be the potential role of ATF2 in tumourigenesis and the sensitivity of ATF2 minus cells/tumours to therapeutic approaches. In addition, mice will be crossed to strains containing alterations in cJun to address the role of ATF2/cJun heterodimer formation.