RT Journal Article
SR Electronic
T1 Proliferative and Antiapoptotic Signaling Stimulated by Nuclear-Localized PDK1 Results in Oncogenesis
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra80
OP ra80
DO 10.1126/scisignal.2003065
VO 5
IS 249
A1 Kikani, Chintan K.
A1 Verona, Erik V.
A1 Ryu, Jiyoon
A1 Shen, Yanying
A1 Ye, Qingqing
A1 Zheng, Li
A1 Qian, Ziliang
A1 Sakaue, Hiroshi
A1 Nakamura, Kyoko
A1 Du, Jie
A1 Ji, Qunsheng
A1 Ogawa, Wataru
A1 Sun, Lu-Zhe
A1 Dong, Lily Q.
A1 Liu, Feng
YR 2012
UL http://stke.sciencemag.org/content/5/249/ra80.abstract
AB Enhanced activation of phosphoinositide 3-kinase (PI3K) is a hallmark of many human tumors because it promotes cell proliferation and survival through several mechanisms. One of these mechanisms is the phosphorylation of the serine and threonine kinase Akt at the cytosolic side of the plasma membrane by phosphoinositide-dependent protein kinase 1 (PDK1), which is recruited and activated by binding to the phosphoinositides produced by PI3K. We previously demonstrated increased nuclear accumulation of PDK1 in cells with enhanced PI3K activity. We report that nuclear PDK1 promoted cell proliferation by suppressing FOXO3A-dependent transcription of the gene encoding p27Kip1 (an inhibitor of cell cycle progression), whereas it enhanced cell survival by inhibiting the activation of c-Jun amino-terminal kinase. Cells with nuclear-localized PDK1 showed anchorage-independent growth, and when injected into mice, these cells induced the formation of solid tumors. In human prostate tumors, cytoplasmic localization of PDK1 correlated only with early-stage, low-risk tumors, whereas nuclear PDK1 localization correlated with high-risk tumors. Together, our findings suggest a role for nuclear-translocated PDK1 in oncogenic cellular transformation and tumor progression in mice and humans.