TY - JOUR
T1 - Reduction of cytosolic p27Kip1 inhibits cancer cell motility, survival, and tumorigenicity
AU - Wu, Frederick Y.
AU - Wang, Shizhen Emily
AU - Sanders, Melinda E.
AU - Shin, Incheol
AU - Rojo, Federico
AU - Baselga, Jose
AU - Arteaga, Carlos L.
PY - 2006/2/15
Y1 - 2006/2/15
N2 - We generated a p27Kip1 mutant (p27ΔNLS) that localized exclusively in cell cytosol. Expression of p27ΔNLS in MCF7 breast cancer cells down-regulated RhoA and increased motility, survival, and Akt levels without an effect on cell cycle distribution. RNA interference of p27 in U87 glioma cells, which express p27 predominantly in the cytoplasm, inhibited motility and survival. Conversely, knockdown of p27 in COS7 cells, with >95% nuclear p27 expression, accelerated proliferation but had no effect on motility or survival. U87 cells in which p27 had been eliminated by RNA interference exhibited lower Akt levels, shorter Akt turnover, and markedly impaired tumorigenicity in vivo. These xenografts were less invasive and exhibited increased apoptosis compared with p27-expressing tumors. Expression of cytosolic p27 in primary human breast carcinomas correlated linearly with Akt content as measured by immunohistochemistry. These data suggest that cytoplasmic p27 can exert oncogenic functions by modulating Akt stability, cell survival, and tumorigenicity.
AB - We generated a p27Kip1 mutant (p27ΔNLS) that localized exclusively in cell cytosol. Expression of p27ΔNLS in MCF7 breast cancer cells down-regulated RhoA and increased motility, survival, and Akt levels without an effect on cell cycle distribution. RNA interference of p27 in U87 glioma cells, which express p27 predominantly in the cytoplasm, inhibited motility and survival. Conversely, knockdown of p27 in COS7 cells, with >95% nuclear p27 expression, accelerated proliferation but had no effect on motility or survival. U87 cells in which p27 had been eliminated by RNA interference exhibited lower Akt levels, shorter Akt turnover, and markedly impaired tumorigenicity in vivo. These xenografts were less invasive and exhibited increased apoptosis compared with p27-expressing tumors. Expression of cytosolic p27 in primary human breast carcinomas correlated linearly with Akt content as measured by immunohistochemistry. These data suggest that cytoplasmic p27 can exert oncogenic functions by modulating Akt stability, cell survival, and tumorigenicity.
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UR - http://www.scopus.com/inward/citedby.url?scp=33644509197&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-3304
DO - 10.1158/0008-5472.CAN-05-3304
M3 - Article
C2 - 16489017
AN - SCOPUS:33644509197
VL - 66
SP - 2162
EP - 2172
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 4
ER -