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Molecular and Cellular Biology, August 2004, p. 6728-6741, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6728-6741.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

In Vivo Mitochondrial p53 Translocation Triggers a Rapid First Wave of Cell Death in Response to DNA Damage That Can Precede p53 Target Gene Activation

Susan Erster,{dagger} Motohiro Mihara,{dagger} Roger H. Kim, Oleksi Petrenko, and Ute M. Moll*

Departments of Pathology and Surgery, Stony Brook University, Stony Brook, New York 11794

Received 30 October 2003/ Returned for modification 7 January 2004/ Accepted 30 April 2004

p53 promotes apoptosis in response to death stimuli by transactivation of target genes and by transcription-independent mechanisms. We recently showed that wild-type p53 rapidly translocates to mitochondria in response to multiple death stimuli in cultured cells. Mitochondrial p53 physically interacts with antiapoptotic Bcl proteins, induces Bak oligomerization, permeabilizes mitochondrial membranes, and rapidly induces cytochrome c release. Here we characterize the mitochondrial p53 response in vivo. Mice were subjected to {gamma} irradiation or intravenous etoposide administration, followed by cell fractionation and immunofluorescence studies of various organs. Mitochondrial p53 accumulation occurred in radiosensitive organs like thymus, spleen, testis, and brain but not in liver and kidney. Of note, mitochondrial p53 translocation was rapid (detectable at 30 min in thymus and spleen) and triggered an early wave of marked caspase 3 activation and apoptosis. This caspase 3-mediated apoptosis was entirely p53 dependent, as shown by p53 null mice, and preceded p53 target gene activation. The transcriptional p53 program had a longer lag phase than the rapid mitochondrial p53 program. In thymus, the earliest apoptotic target gene products PUMA, Noxa, and Bax appeared at 2, 4, and 8 h, respectively, while Bid, Killer/DR5, and p53DinP1 remained uninduced even after 20 h. Target gene induction then led to further increase in active caspase 3. Similar biphasic kinetics was seen in cultured human cells. Our results suggest that in sensitive organs mitochondrial p53 accumulation in vivo occurs soon after a death stimulus, triggering a rapid first wave of apoptosis that is transcription independent and may precede a second slower wave that is transcription dependent.

* Corresponding author. Mailing address: Department of Pathology, BST 9, Stony Brook University, Stony Brook, NY 11794-8691. Phone: (631) 444-2459. Fax: (631) 444-3424. E-mail: umoll{at}notes.sunysb.edu.

{dagger} S.E. and M.M. contributed equally to this work.

Molecular and Cellular Biology, August 2004, p. 6728-6741, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6728-6741.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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