¹Department of Pathology, Stony Brook University, SUNY at Stony Brook, Stony Brook, NY, USA

Correspondence: Dr UM Moll, Department of Pathology, Stony Brook University, SUNY at Stony Brook, BSTL9, Room 134, Stony Brook, NY 11794-8691, USA. E-mail: umoll@notes.cc.sunysb.edu

Received 9 November 2005; Revised 20 March 2006; Accepted 29 March 2006; Published online 8 May 2006.

Abstract

The complex apoptotic functions of the p53 tumor suppressor are central to its antineoplastic activity in vivo. Besides its well-known action as a transcriptional activator of apoptotic genes, p53 exerts a direct proapoptotic role at the mitochondria via protein–protein interactions with Bcl2 family members, thus executing the shortest known circuitry of p53 death signaling. We recently reported that exclusive delivery of p53 to mitochondria exerts a significant in vivo tumor suppressor activity in p53-null lymphomas. However, it was unknown whether mitochondrially targeted p53 has suppressor activities in tumors harboring missense mutants, which constitute the vast majority of p53 alterations in human tumors. Here, we show that targeting p53 to mitochondria does confer a significant growth disadvantage in B-lymphomas expressing various point mutants of p53, resulting in efficient apoptosis induction in vitro and in vivo in mice.