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.
journal_name
Celljournal_title
Cellauthors
Lau E,Kluger H,Varsano T,Lee K,Scheffler I,Rimm DL,Ideker T,Ronai ZAdoi
10.1016/j.cell.2012.01.016subject
Has Abstractpub_date
2012-02-03 00:00:00pages
543-55issue
3eissn
0092-8674issn
1097-4172pii
S0092-8674(12)00022-0journal_volume
148pub_type
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