Serine 392 phosphorylation modulates p53 mitochondrial translocation and transcription-independent apoptosis

Cédric Castrogiovanni, Béranger Waterschoot, Olivier De Backer, Patrick Dumont

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Abstract

The tumor suppressor p53 is a key regulator of apoptosis induced by various cellular stresses. p53 can induce apoptosis by two mechanisms. First, p53 acts as a transcription factor inducing and repressing pro-apoptotic and anti-apoptotic targets genes, respectively. Second, p53 is able to translocate to the mitochondria, where it interacts with BCL-2 family members to induce membrane permeabilization and cytochrome c release. p53 transcriptional activity is regulated by a set of post-translational modifications that have been well documented. However, how these modifications impact the direct mitochondrial pathway of death remain poorly understood. In this study, we focused on the role of serine 392 phosphorylation in the control of p53-dependent apoptosis. We used CRISPR/Cas9 genome editing to substitute serine 392 by a non-phosphorylatable alanine in HCT-116 colon carcinoma cells. The S392A mutant displayed normal transcriptional activity following genotoxic stress, but markedly impaired ability to localize to mitochondria. The decreased mitochondrial localization of the S392A mutant correlated with a lower ability to induce apoptosis. Confirmatory observations were made following enforced expression of the S392A p53 mutant or a phospho-mimetic S392E mutant in H1299 lung carcinoma cells. Our observations support the premise that serine 392 phosphorylation of p53 influences its mitochondrial translocation and transcription-independent apoptotic function.

Original languageEnglish
Pages (from-to)190-203
Number of pages14
JournalCell death and differentiation
Volume25
Issue number1
Early online date22 Sep 2017
DOIs
Publication statusPublished - Jan 2018

Keywords

  • Apoptosis
  • Apoptosis Regulatory Proteins/metabolism
  • CRISPR-Cas Systems
  • Camptothecin/toxicity
  • Humans
  • Mitochondria/chemistry
  • Mutation
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Transport
  • Serine/metabolism
  • Transcription, Genetic
  • Tumor Suppressor Protein p53/chemistry

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