p53 has a direct apoptogenic role at the mitochondria

Motohiro Mihara, Susan Erster, Alexander Zaika, Oleksi Petrenko, Thomas Chittenden, Petr Pancoska, Ute M. Moll

Research output: Contribution to journalArticle

1356 Scopus citations

Abstract

p53 induces apoptosis by target gene regulation and transcription-independent signaling. However, a mechanism for the latter was unknown. We recently reported that a fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. Here, we provide evidence that p53 translocation to the mitochondria occurs in vivo in irradiated thymocytes. Further, we show that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BclXL and Bcl2 proteins, resulting in cytochrome c release. p53 binds to BclXL via its DNA binding domain. We probe the significance of mitochondrial p53 and show that tumor-derived transactivation-deficient mutants of p53 concomitantly lose the ability to interact with BclXL and promote cytochrome c release. This opens the possibility that mutations might represent "double-hits" by abrogating the transcriptional and mitochondrial apoptotic activity of p53.

Original languageEnglish (US)
Pages (from-to)577-590
Number of pages14
JournalMolecular Cell
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P., & Moll, U. M. (2003). p53 has a direct apoptogenic role at the mitochondria. Molecular Cell, 11(3), 577-590. https://doi.org/10.1016/S1097-2765(03)00050-9