Death Signal-induced Localization of p53 Protein to Mitochondria

By N. Marchenko, A. Zaika, U. Moll. Journal of Biological Chemistry, 2000

975 citations recorded by the source corpus.

The mechanism of p53-mediated apoptosis after cellular stress remains poorly understood. Evidence suggests that p53 induces cell death by a multitude of molecular pathways involving activation of target genes and transcriptionally independent direct signaling. Mitochondria play a key role in apoptosis. We show here that a fraction of p53 protein localizes to mitochondria at the onset of p53-dependent apoptosis but not during p53-independent apoptosis or p53-mediated cell cycle arrest. The accumulation of p53 to mitochondria is rapid (within 1 h after p53 activation) and precedes changes in mitochondrial membrane potential, cytochromec release, and procaspase-3 activation. Immunoelectron microscopy and immuno-fluorescence-activated cell sorter analysis of isolated mitochondria show that the majority of mitochondrial 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 again partially localizes to mitochondria, preceding the onset of apoptosis. Overexpression of anti-apoptotic Bcl-2 or Bcl-xL abrogates stress signal-mediated mitochondrial p53 accumulation and apoptosis but not cell cycle arrest, suggesting a feedback signaling loop between p53 and mitochondrial apoptotic regulators. Importantly, bypassing the nucleus by targeting p53 to mitochondria using import leader fusions is sufficient to induce apoptosis in p53-deficient cells. We propose a model where p53 can contribute to apoptosis by direct signaling at the mitochondria, thereby amplifying the transcription-dependent apoptosis of p53.

Subfields: Biotechnology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/a345fa1a2b9f218a946551985a1dbf5644d787fd

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biotechnology

In Molecular Biology

In Oncology

Citations in the corpus

The codon 72 polymorphic variants of p53 have markedly different apoptotic potential (2003, background): “A percentage of p53 localizes to the mitochondria after an apoptotic stimulus, and this localization is influential in p53-dependent apoptosi”
Organelle-specific initiation of cell death pathways (2001, background): “One such mechanism might involve the translocation of p53 to mitochondria, where it locates both at the surface and within the organelle, interacting with mitochondrial Hsp70 (ref”
The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. (2016, background): “A fraction of p53 protein can be detected at the mitochondria following DNA damage, preceding the loss of mitochondrial transmembrane potential and caspase activation (Marchenko et al. 2000; Mihara et al. 2003).”
Viruses and apoptosis (2001, background): “Interestingly, a growing number of apoptotic messengers, including transcription factors (Li et al. 2000) and p53 (Marchenko et al. 2000), have now been shown to share the capacity to translocate to the mitochondrial membrane, although the mechanisms by which this occurs are not clear.”
The BCL-2 Family Reunion (2010, background): “The involvement of mitochondria in this pathway was elucidated when a fraction of stabilized p53 localized with mitochondria following genotoxic stress (Marchenko et al., 2000).”
The expanding role of mitochondria in apoptosis. (2001, background): “…including p53 itself, an orphan receptor TR3, the p53-target gene p53AIP, and the Peutz-Jegher gene product LKB1 have been shown to migrate to the mitochondria during apoptosis and to cause mitochondrial damage (Li et al. 2000; Marchenko et al. 2000; K. Oda et al. 2000; Karuman et al. 2001).”
p53 polymorphisms: cancer implications (2009, neutral): “i1 i2 i3 i4 i5 i6 i7 i8 i9 i10 (41, 10,739) (1, 115) (2, 92) (5, 775) (2, 81) (4, 567) (7, 342) (1, 92) (13, 2,817) (5, 919) Transactivation domains Prolinerich domain DNA-binding domain Tetramerization domain”
DNA damage-induced apoptosis (2004, background): “In addition p53 itself has been shown to bind DNA strand breaks (Bakalkin et al., 1994), suggesting a possible role in DNA damage detection, or to translocate to mitochondria specifically during p53-dependent apoptosis (Marchenko et al., 2000; Mihara et al., 2003).”
The mitochondrial p53 pathway (2008, positive): “In addition, it is imported into the mitochondrial matrix (presumably via the TOM/TIM complex), where the leader is cleaved off by endopeptidases prior to p53 redistribution within the submitochondrial compartments [7].”
p53: death star. (2000, neutral): “p53 itself to the mitochondria (Marchenko et al., 2000).”
Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis (2006, background): “For instance, recent studies demonstrated that a fraction of p53 translocates to mitochondria during stress-induced apoptosis, but not during growth arres”