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PMID:22304920

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Citation

Lau, E, Kluger, H, Varsano, T, Lee, K, Scheffler, I, Rimm, DL, Ideker, T and Ronai, ZA (2012) PKCε promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Cell 148:543-55

Abstract

The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress. The ability of ATF2 to reach the mitochondria is determined by PKCε, which directs ATF2 nuclear localization. Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor samples, high PKCε levels associate with poor prognosis. Overall, our findings provide the framework for understanding how subcellular localization enables ATF2 oncogenic or tumor suppressor functions.

Links

PubMed Online version:10.1016/j.cell.2012.01.016

Keywords

Activating Transcription Factor 2/metabolism; Apoptosis; Cell Line; Cell Line, Tumor; Cell Nucleus/metabolism; Cytosol/metabolism; DNA Damage; Fibroblasts/metabolism; Hexokinase/metabolism; Humans; Melanoma/metabolism; Mitochondria/metabolism; Prognosis; Protein Kinase C-epsilon/metabolism; Protein Transport; Voltage-Dependent Anion Channel 1/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ATF2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ATF2

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ATF2

involved_in

GO:0006974: cellular response to DNA damage stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ATF2

involved_in

GO:0006355: regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ATF2

located_in

GO:0005741: mitochondrial outer membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ATF2

involved_in

GO:1902110: positive regulation of mitochondrial membrane permeability involved in apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KPCL

involved_in

GO:0006468: protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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