title: P21-activated kinase 4 regulates the cyclin-dependent kinase inhibitor p57(kip2) in human breast cancer.
abstract: 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.
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, 110001, China.
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Li
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Cheng
authors.forename: Guanqiao
authors.initials: G
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D012333:RNA, Messenger; D025801:Ubiquitin; C116367:PAK4 protein, human; D054462:p21-Activated Kinases; D046988:Proteasome Endopeptidase Complex
keywords: PAK4; cell cycle; degradation; p57Kip2; ubiquitination