TY - JOUR
T1 - PKCε promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria
AU - Lau, Eric
AU - Kluger, Harriet
AU - Varsano, Tal
AU - Lee, Kiyoung
AU - Scheffler, Immo
AU - Rimm, David L.
AU - Ideker, Trey
AU - Ronai, Ze'Ev A.
N1 - Funding Information:
We thank Meenhard Herlyn and John Clifford for melanoma and SCC cell lines, Jorge Moscat and Maria Diaz-Meco for PKC reagents, members of the Salvesen lab, Robbin Newlin and Yoav Altman for technical assistance, and Colin Goding for helpful comments on the manuscript. We also thank Ronai laboratory members, Meifan Chen, Hyungsoo Kim, Ersheng Kuang, Marzia Scortegagna, and Meera Shah for technical advice and assistance and Gustavo Gutierrez for bacterial ATF2 proteins. Support from ACS Postdoctoral Fellowship, Illinois Division and NCI T32 training grant (117090-PF-09-112-01-GMC and 5-T32-CA121949 to E.L.) and NCI grants (CA099961 and CA051995 to Z.A.R.) are gratefully acknowledged. D.L.R. is a consultant for and stockholder in HistoRx, the exclusive licensee of the Yale-owned AQUA technology used in this work.
PY - 2012/2/3
Y1 - 2012/2/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84863012289&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.01.016
DO - 10.1016/j.cell.2012.01.016
M3 - Article
C2 - 22304920
AN - SCOPUS:84863012289
SN - 0092-8674
VL - 148
SP - 543
EP - 555
JO - Cell
JF - Cell
IS - 3
ER -