PKCε promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria.
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.
Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Eric
E
Lau
Harriet
H
Kluger
Tal
T
Varsano
KiYoung
K
Lee
Immo
I
Scheffler
David L
DL
Rimm
Trey
T
Ideker
Ze'ev A
ZA
Ronai
D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D011379:Prognosis; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D021381:Protein Transport; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
D051698:Activating Transcription Factor 2; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1; C472074:HK1 protein, human; D006593:Hexokinase; D051744:Protein Kinase C-epsilon