Nd. Marchenko et al., Death signal-induced localization of p53 protein to mitochondria - A potential role in apoptotic signaling, J BIOL CHEM, 275(21), 2000, pp. 16202-16212
The mechanism of p53-mediated apoptosis after cellular stress remains poorl
y understood. Evidence suggests that p53 induces cell death by a multitude
of molecular pathways involving activation of target genes and transcriptio
nally independent direct signaling. Mitochondria play a key role in apoptos
is, We show here that a fraction of p53 protein localizes to mitochondria a
t the onset of p53-dependent apoptosis but not during p53-independent apopt
osis or p53-mediated cell cycle arrest. The accumulation of p53 to mitochon
dria is rapid (within 1 h after p53 activation) and precedes changes in mit
ochondrial membrane potential, cytochrome c release, and procaspase-3 activ
ation. Immunoelectron microscopy and immuno-fluorescence-activated cell sor
ter analysis of isolated mitochondria show that the majority of mitochondri
al p53 localizes to the membranous compartment, whereas a fraction is found
in a complex with the mitochondrial import motor mt hsp70, After induction
of ectopic p53 without additional DNA damage in p53-deficient cells, p53 a
gain partially localizes to mitochondria, preceding the onset of apoptosis,
Overexpression of anti-apoptotic Bcl-2 or Bcl-xL abrogates stress signal-m
ediated mitochondrial p53 accumulation and apoptosis but not cell cycle arr
est, suggesting a feedback signaling loop between p53 and mitochondrial apo
ptotic regulators. Importantly, bypassing the nucleus by targeting p53 to m
itochondria using import leader fusions is sufficient to induce apoptosis i
n p53-deficient cells. We propose a model where p53 can contribute to apopt
osis by direct signaling at the mitochondria, thereby amplifying the transc
ription-dependent apoptosis of p53.