Enabling death by the Abl tyrosine kinase: mechanisms for nuclear shuttling of c-Abl in response to DNA damage.
c-Abl is a ubiquitously expressed tyrosine kinase that participates in a diverse array of cellular signaling cascades. The cellular response elicited by c-Abl depends upon its location in cells. Retention of c-Abl in the cytoplasm results in cell proliferation and survival. By contrast, nuclear c-Abl becomes activated and induces apoptosis following genotoxic stress. We recently demonstrated the molecular mechanisms by which c-Abl shuttles into the nucleus in response to DNA damage. In normal cells, 14-3-3 proteins sequester c-Abl in the cytoplasm. Upon exposure of cells to DNA damaging agents, JNK is activated and phosphorylates 14-3-3, resulting in the release of c-Abl into the nucleus. Importantly, nuclear targeting of c-Abl is required for the induction of apoptosis in response to DNA damage. Thus, c-Abl may function in determining cell fate via its subcellular localization. In this review, we focus on the implications of these findings on our understanding of Abl-regulated cellular functions and on potential therapeutic strategies to manipulate the aberrant kinase.
Yoshida
Kiyotsugu
K
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. yos.mgen@mri.tmd.ac.jp
Miki
Yoshio
Y
D021581:Active Transport, Cell Nucleus; D001692:Biological Transport; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*
D016315:Proto-Oncogene Proteins c-abl