1. ¹Department of Pathology, Division of Neuropathology, University of Alabama at Birmingham, SC 961, 1530 3rd Avenue South, Birmingham, AL 35294-0017, USA
2. ²Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: KA Roth, Department of Pathology, Division of Neuropathology, University of Alabama at Birmingham, SC 961, 1530 3rd Avenue South, Birmingham, AL 35294-0017, USA. Tel: +205-934-5802; Fax: +205-934-6700; E-mail: kroth@path.uab.edu

Received 23 August 2005; Revised 22 November 2005; Accepted 21 December 2005; Published online 3 March 2006.

Abstract

Neural precursor cells (NPCs) are markedly sensitive to apoptotic insults. p53-dependent transcriptional activation of proapoptotic genes has been hypothesized to regulate NPC death in response to DNA damage. Recent studies of non-NPCs have also indicated that p53 may directly interact with Bcl-2 molecules and thereby regulate death independently of transcription. The contribution of transcription-independent p53 activation in NPC death has not been characterized. In this study, we found that apoptosis caused by chemotherapeutic agents in NPCs required p53 expression and new macromolecular synthesis. In contrast, NPC death induced by staurosporine, a broad kinase inhibitor, is regulated by p53 in the absence of macromolecular synthesis. The apoptosis effector molecules Bax and Bak, Apaf-1, and caspase-9 were shown to be downstream of p53 in both pathways. These findings indicate that p53 is in a unique position to regulate at least two distinct signaling portals that activate the intrinsic apoptotic death pathway in NPCs.