MOUSE BRN-3 FAMILY OF POU TRANSCRIPTION FACTORS - A NEW AMINOTERMINALDOMAIN IS CRUCIAL FOR THE ONCOGENIC ACTIVITY OF BRN-3A

The class IV POU domain genes Brn-3a, -b and -c are differentially exp ressed during neural development and at least Brn-3a also in neuroecto dermal tumors. In contrast to Brn-3b and Brn-3c, Brn-3a encodes two pr otein variants: Brn-3a(I) and Brn-3a(s). Brn-3a(s) lacks 84 aminotermi nal residues but is otherwise identical to Brn-3a(I). Outside the well conserved carboxyterminal POU domains all three Brn-3 proteins (-a, - b and -c) diverge until the aminoterminal end where a new domain of ab out 100 amino acids is identified. This domain is conserved only betwe en Brn-3 proteins and other class IV POU factors. Brn-3a(I) that conta ins the complete domain but not Brn-3a(s) that lacks 84 amino acids of it is able to tumorigenically transform primary fibroblasts. Brn-3b t hat lacks 40 amino acids of the new domain does itself not transform, but abolishes the oncogenic potential of Brn-3a(I) when transfected to gether. This demonstrates not only that Brn-3a(I) is a proto-oncogene and may well be causally involved in the generation of neuroectodermal tumors but also suggests that the intactness of the new aminoterminal domain described here is crucial for oncogenic activity. In addition, our data indicate that Brn-3b acts as an inhibitor of Brn-3a(I) activ iy.