Livingstone, Catherine Mary; (1995) Functional characterization of the ATF2 transcription factor. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

ATF2 (CRE-BP1, CREB2) is a member of the bzip family of transcription factors which are characterized by their ability to bind to a CRE/ATF site. At least ten different mammalian cDNAs of this family have been cloned and the transcriptional and regulatory properties of some members determined by transient transfection assays. Such studies have implicated ATF2 in transcriptional activation by the adenovirus E1a protein. Previous mutational analysis of ATF2 revealed the importance of an N-terminal region for activation by E1a. In this thesis I have carried out a more detailed investigation of this region and found that a segment consisting of amino acid residues 19-96 can act as a very potent transactivation domain when fused to a heterologous DNA binding moiety. This strong activation is seen in the absence of E1a and is not greatly enhanced by E1a. Since this domain does not activate transcription in the context of the full length protein, it appears to be "masked" in some, as yet, unknown way. The activation domain contains a zinc finger and three potential MARK sites at positions 69, 71 and 90. Mutating any of these motifs reduces the activity of the domain, with the threonine residues at positions 69 and 71 being the most critical for its function. The use of serum/UV stimulation experiments and MARK site mutants has shown that phosphorylation of this domain is important for regulating its activity in vivo and therefore suggest that ATF2 plays a role in signal transduction. The features required for activation by the N-terminus of ATF2 (zinc finger and phosphorylation sites) are also important for Ela activation of transcription via full length ATF2. The implications of these results with regard to a model for E1a transactivation are presented in this thesis.

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