Premium
P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57 Kip2 in Human Breast Cancer
Author(s) -
Li Yanshu,
Wang Di,
Zhang Hongyan,
Wang Chunyu,
Dai Wei,
Cheng Zhenguo,
Wang Guanqiao,
Li Feng
Publication year - 2013
Publication title -
the anatomical record
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.678
H-Index - 62
eISSN - 1932-8494
pISSN - 1932-8486
DOI - 10.1002/ar.22754
Subject(s) - mg132 , kinase , small interfering rna , cancer research , cell cycle , cell growth , cyclin dependent kinase 4 , proteasome , gene knockdown , cyclin dependent kinase 2 , microbiology and biotechnology , protein kinase a , biology , chemistry , cell , cell culture , proteasome inhibitor , biochemistry , transfection , genetics
The p21‐activated kinases have been implicated in the control of cell cycle progression. However, the biological mechanism underlying the role of p21‐activated kinase 4 (PAK4) in cell cycle control remains unknown. Here, by using quantitative RT–PCR and immunoblot analyses, we discovered that over‐expression of PAK4 could suppress cyclin‐dependent kinase inhibitor 1C (p57 Kip2 ) expression in the MCF‐7 human breast cancer cell line, whereas lentiviral vector‐mediated small interfering RNA (siRNA) knockdown of PAK4 markedly promoted p57 Kip2 expression in MCF‐7 cells. Furthermore, PAK4‐mediated down‐regulation of p57 Kip2 was reversed by MG132, a specific proteasome inhibitor. The ubiquitination assay confirmed that the activity of PAK4 attenuated p57 Kip2 protein stability through the ubiquitin‐proteasome pathway in MCF‐7 cells. Moreover, a significant inverse correlation between PAK4 and p57 Kip2 protein levels was observed in breast cancer tissues by immunohistochemical analysis. Taken together, our data demonstrate a novel function for PAK4 in regulating the stability of p57 Kip2 , possibly through the ubiquitin‐proteasome pathway, leading to increased proliferation of breast cancer cells. Thus, PAK4 may be used as a potential diagnostic and therapeutic target for human breast cancer. Anat Rec, 296:1561–1567, 2013. © 2013 Wiley Periodicals, Inc.