BCL-2 TRANSCRIPTION FROM THE PROXIMAL P2 PROMOTER IS ACTIVATED IN NEURONAL CELLS BY THE BRN-3A POU FAMILY TRANSCRIPTION FACTOR

The BCL-2 protein is able to protect neuronal and other cell types fro m apoptotic programmed cell death and plays a key role in regulating t he rate of apoptosis during development of the nervous system. We have previously demonstrated that the Brn-3a POU domain transcription fact or protects sensory neurons from apoptotic programmed cell death induc ed by nerve growth factor withdrawal. We report here that Bcl-2 transc ription is predominantly initiated from the Bcl-2 Pa promoter in both the ND7 neuronal cell line and primary dorsal root ganglion neurons, i n contrast to the predominant use of the Bcl-2 P1 promoter in other ce ll types. Moreover, Bcl-2 transcription initiated from the P2 region i ncreases in ND7 cells stably overexpressing Brn-3a, resulting in enhan ced BCL-2 protein levels. Similarly, the Bcl-2 P2 promoter is directly activated by Brn-3a in co-transfection assays in both ND7 cells and d orsal, root ganglion neurons. Analysis of the Bcl-2 regulatory sequenc e revealed a binding site for Brn-3a that is required for maximal acti vation by Brn-3a both in transfected cells and during differentiation of ND7 cells. Together these data identify Brn-3a as the first transcr iption factor regulating Bcl-2 activity specifically in neuronal cells and indicate that the anti-apoptotic effect of Brn-3a is likely to be mediated, at least in part, via the up-regulation of Bcl-2 expression .