Reduction of cytosolic p27(Kip1) inhibits cancer cell motility, survival, and tumorigenicity.
We generated a p27(Kip1) mutant (p27deltaNLS) that localized exclusively in cell cytosol. Expression of p27deltaNLS 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.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Frederick Y
FY
Wu
Shizhen Emily
SE
Wang
Melinda E
ME
Sanders
Incheol
I
Shin
Federico
F
Rojo
Jose
J
Baselga
Carlos L
CL
Arteaga
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019556:COS Cells; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002522:Chlorocebus aethiops; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D014162:Transfection; D014183:Transplantation, Heterologous; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics
D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; D020742:rhoA GTP-Binding Protein