Stress-induced p53 runs a transcription-independent death program
Susan Erster, Ute M. Moll
*
Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
Received 29 March 2005
Available online 5 April 2005
Abstract
The transcription-independent p53-mediated apoptotic response has obtained a solid mechanistic basis in recent years. A fraction
of stress-induced wild type p53 protein rapidly translocates to mitochondria in response to genotoxic, hypoxic, and oxidative stresses
in established cell lines and primary cells, as well as in physiological and pathophysiologic stress responses in the animal. While the
groundwork of mechanisms and kinetics of direct mitochondrial p53 activities is laid out, the quantitative contribution of this path-
way to total p53-mediated apoptosis and tumor suppression in vivo remains to be elucidated. An update on these efforts is given
here.
Ó 2005 Elsevier Inc. All rights reserved.
Keywords: p53; Mitochondria; bcl2 protein family
Death signal-induced mitochondrial translocation of p53
Based on earlier reports of transcription-independent
killing actions of p53 and the pivotal importance of the
mitochondrial death pathway in p53-dependent apopto-
sis, we investigated the possibility that, in addition to its
transactivation role in the nucleus (and in some circum-
stances transrepression), p53 might have a direct role at
mitochondria. To this end, isolated mitochondria, along
with other subcellular fractions, from cells before and
briefly after DNA damage or hypoxic stress were ana-
lyzed by p53 immunoblots and correlated to their apop-
totic response. Our results demonstrate that a highly
reproducible fraction of stress-induced wild type p53
protein traffics to mitochondria at the onset of p53-
dependent apoptosis [1]. We initially demonstrated
mitochondrial p53 translocation in the human myeloid
leukemia line ML-1, the colorectal carcinoma line
RKO, and the human breast cancer cell line MCF-7, fol-
lowing apoptosis induction by DNA damage or hypoxic
stress [1,2]. Identical results were also seen with mouse
immortal myeloid progenitors 32D and the preB-cells
Baf3. This suggests that mitochondrial p53 accumula-
tion is a widespread phenomenon that might occur in
vivo during various types of stress responses and across
species in non-malignant and malignant cells.
In support of a specific role for mitochondrial p53
translocation in p53-mediated apoptosis was the fact
that this phenomenon was stress-inducible. Moreover,
although mitochondria are also a downstream compo-
nent of the TNF/DISC/procaspase 8 pathway,
mitochondrial translocation did not occur in p53-inde-
pendent death via the TNF pathway. ML1 cells, fol-
lowing treatment with TNF-a (plus the obligatory
actinomycin D to inhibit the NFjB pathway, which
incidentally induces very high total cellular levels of
p53), failed to undergo translocation. Furthermore,
ML1 cells treated with nanomolar doses of Actinomy-
cin D to induce p53-mediated cell cycle arrest failed to
undergo p53 translocation. Likewise, immortal human
diploid fibroblast lines IMR90 and MRC5, as well as
0006-291X/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.bbrc.2005.03.187
*
Corresponding author. Fax: +1 631 444 3424.
E-mail address: umoll@notes.cc.sunysb.edu (U.M. Moll).
www.elsevier.com/locate/ybbrc
Biochemical and Biophysical Research Communications 331 (2005) 843–850
BBRC