Negative cell cycle regulator 14-3-3sigma stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt.
The 14-3-3sigma (sigma) protein is a human cancer marker downregulated in various tumors, but its function has not been fully established. 14-3-3sigma is a negative regulator of cell cycle when overexpressed, but it is not clear whether 14-3-3sigma regulates cyclin-dependent kinase inhibitor p27(Kip1) to negatively affect cell cycle progression. Protein kinase B/Akt is a crucial regulator of oncogenic signal and can phosphorylate p27(Kip1) to enhance p27(Kip1)degradation, thereby promoting cell growth. Here, we show that 14-3-3sigma-mediated cell cycle arrest concurred with p27(Kip1) upregulation and Akt inactivation. We show that 14-3-3sigma blocks Akt-mediated acceleration of p27(Kip1) turnover rate. 14-3-3sigma inhibits Akt-mediated p27(Kip1) phosphorylation that targets p27(Kip1) for nuclear export and degradation. 14-3-3sigma inhibits cell survival and tumorigenicity of Akt-activating breast cancer cell. Low expression of 14-3-3sigma in human primary breast cancers correlates with cytoplasmic location of p27(Kip1). These data provide an insight into 14-3-3sigma activity and rational cancer gene therapy by identifying 14-3-3sigma as a positive regulator of p27 and as a potential anticancer agent.
Yang
H
H
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Zhang
Y
Y
Zhao
R
R
Wen
Y-Y
YY
Fournier
K
K
Wu
H-B
HB
Yang
H-Y
HY
Diaz
J
J
Laronga
C
C
Lee
M-H
MH
D048948:14-3-3 Proteins; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005092:Exonucleases / Q000378:metabolism*; D005095:Exoribonucleases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008907:Mink; D009363:Neoplasm Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human