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ATF2 - a HLH bZIP transcription factor mediates its transcriptional functions upon its heterodimerization with other members of the bZIP family, as primarily demonstrated for c-Jun. For its transcriptional function, ATF2 needs to be phosphorylated by JNK or p38, on N-terminal residues. We found that ATF2 is also subject to modification by ATM (and possibly other members of the PIKK family), whereby it is recruited to DNA damage repair foci (MRN complex) within a few minutes after exposure to DNA damage. ATF2 phosphorylation by ATM occurs on its C-terminal end and is independent of JNK/p38 activities. This study was published in the journal Molecular Cell in 2005.

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. Read more (Cell, 2012)