Viral and cellular oncogenes induce rapid mitochondrial translocation of p53 in primary epithelial and endothelial cells early in apoptosis.
In p53-dependent apoptosis in response to genotoxic and hypoxic stress, a fraction of induced wild-type p53 rapidly translocates to mitochondria, triggering a rapid first wave of mitochondrial membrane permeabilization and apoptosis that is later fortified by the transcriptional program of p53. However, whether this direct mitochondrial program also occurs upon oncogenic stress is unknown. In normal cells, oncogenic signals can induce a p53-dependent fail-safe mechanism to counter uncontrolled proliferation by engaging p53-dependent apoptosis. To address whether mitochondrial p53 contributes to oncogene-induced fail-safe apoptosis, p53 translocation was determined in primary human epithelial and endothelial cells overexpressing c-Myc, E1A or E2F1. Serum starvation of these cells, but not of control cells, triggered rapid p53 accumulation at mitochondria, accompanied by cytochrome c and SMAC release and followed by apoptosis. Our data establishes the contribution of the transcription-independent mitochondrial p53 pathway to apoptosis of primary cells in response to deregulated oncogenes.
Nemajerova
Alice
A
Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, New York 11794-8691, USA.
Wolff
Sonja
S
Petrenko
Oleksi
O
Moll
Ute M
UM
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D017502:Adenovirus E2 Proteins / Q000235:genetics / Q000378:metabolism; D017456:Adenovirus Early Proteins / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D042783:Endothelial Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; D017502:Adenovirus E2 Proteins; D017456:Adenovirus Early Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53