Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells.
The transcription factor KLF5 plays an important role in human carcinogenesis. In epithelial cells, the KLF5 protein is tightly regulated by the ubiquitin-proteasome pathway. To better understand the mechanisms for the regulation of KLF5 protein, we identified and characterized an E3 ubiquitin ligase for KLF5, i.e. WWP1. We found that WWP1 formed a protein complex with KLF5 in vivo and in vitro. Furthermore, WWP1 mediated the ubiquitination and degradation of KLF5, and the catalytic cysteine residue of WWP1 is essential for its function. A PY motif in a transactivation domain of KLF5 is necessary for its interaction with WWP1. Finally, WWP1 was amplified and overexpressed in some cancer cell lines from the prostate and breast, which negatively regulated the function of KLF5 in gene regulation. These findings not only established WWP1 as an E3 ubiquitin ligase for KLF5, they also further implicated the KLF5 pathway in human carcinogenesis.
Chen
Ceshi
C
Winship Cancer Institute and Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Sun
Xiaodong
X
Guo
Peng
P
Dong
Xue-Yuan
XY
Sethi
Pooja
P
Cheng
Xiaohong
X
Zhou
Jun
J
Ling
Junxiu
J
Simons
Jonathan W
JW
Lingrel
Jerry B
JB
Dong
Jin-Tang
JT
D020816:Amino Acid Motifs; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D002384:Catalysis; D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism
C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D012313:RNA; D004247:DNA; D008156:Luciferases; C471642:WWP1 protein, human; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase; D046988:Proteasome Endopeptidase Complex; D003545:Cysteine