Tumorigenic effect of transcription factor hAP-2alpha and the intricate link between hAP-2alpha activation and squelching.

Overexpression of human activator protein-2alpha (hAP-2alpha) is carcinogenic. Its aberrant regulation is the underlying tumorigenic event in the human teratocarcinoma cell line PA-1. In this cell line excess hAP-2alpha protein binds and sequesters coactivators, which interferes with the activity of other activators and with its own activity. The N-terminus of hAP-2alpha, which contains an activation domain, is critical in squelching and tumorigenicity. Mutation analyses of the N-terminus region showed that activation and squelching were intricately linked; nevertheless, squelching could occur in the absence of activity. Cells overexpressing squelching-proficient mutants grew efficiently on soft agar irrespective of their ability to activate transcription, which indicates that these cells are tumorigenic. Mutants that lacked both properties were nontumorigenic. These results suggest that squelching, but not activation, causes transformation and that the factors that are sequestered at this region are critical in tumorigenesis.