Translocation of p53 to mitochondria is regulated by its lipid binding property to anionic phospholipids and it participates in cell death control

Ching H. Li, Yu W. Cheng, Po Ling Liao, Jaw J. Kang

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

p53, can regulate cell apoptosis in both transcription-dependent and -independent manners. The transcription-independent pathway was demonstrated by the translocation of p53 to mitochondria. Our study showed that p53 mitochondrial translocation was found in mitomycin C (MMC)-treated HepG2. The p53 C-terminal domain is clustered with potential nuclear leading sequences and showed strong electrostatic ion-ion interactions with cardiolipin, phosphatidylglycerol and phosphatidic acid in vitro. Disruption of cardiolipin biosynthesis by phosphatidylglycerophosphate synthase (PGS) or CDP-diacylglycerol synthase 2 (CDS-2) short hairpin RNA (shRNA) transfection eliminated the MMC-induced translocation of mitochondrial p53. The elimination of mitochondrial p53 translocation also reduced Bcl-xL and Bcl-2 mitochondrial distribution. In HEK 293T models with saturated p53 expression, the mitochondrial partition of p53, Bcl-xL, and Bcl-2 obviously decreased in their PGS shRNA- or CDS-2 shRNA-expressing stable clones. In p53-null H1299 models, both the mitochondrial partitions of Bcl-xL and Bcl-2 were strongly reduced in relation to the HEK 293T models. The Bcl-xL mitochondrial partition was elevated in H1299 models expressing pCEP4-p53wt suggesting the direct carrier role of p53 in transporting Bcl-xL to the mitochondria. We also found that the cytosolic pool of Bcl-xL and Bcl-2 remained unaffected in the low-dose MMC treatment but decreased in the high-doseMMCtreatment. The cytosolic pool of Bcl-2 and Bcl-xL directly regulated theiramounts in p53-dependent mitochondrial distribution. In the low-dose MMC treatment, the increased mitochondrial p53, Bcl-xL, and Bcl-2 could attenuate apoptosis. However, in the high-dose MMC treatment, only the p53 translocated to the mitochondria and resulted in apoptosis progression. Onthe basis of this study,we thought mitochondrial p53 might regulate apoptosis in a biphasic manner.

Original languageEnglish
Pages (from-to)150-160
Number of pages11
JournalNeoplasia (New York, N.Y.)
Volume12
Issue number2
DOIs
Publication statusPublished - Feb 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research

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