CHFR functions as a ubiquitin ligase for HLTF to regulate its stability and functions.
CHFR functions as a mitotic checkpoint by delaying entry into metaphase in response to mitotic stress. CHFR is frequently silenced by hypermethylation in human cancers, indicating that CHFR is a tumor suppressor. To further elucidate the role of CHFR in tumorigenesis, we studied the relationship between CHFR and a novel CHFR-interacting protein, HLTF, helicase-like transcription factor. Here we show that CHFR binds to and ubiquitinates HLTF, leading to its degradation. HLTF modulates basal expression of PAI-1 involved in regulation of cell migration. Consistently, overexpression of CHFR inhibits cell migration, resulting from reduced HLTF followed by decreased PAI-1 expression. HLTF expression is also higher in human breast cancer cells where CHFR is not expressed. Taken together, this is the first report identifying the regulatory mechanism of HLTF by CHFR, suggesting that CHFR-mediated downregulation of HLTF may help protect against cancer.
Kim
Joo Mi
JM
School of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Seoul 151-742, Republic of Korea.
Cho
Eun Nae
EN
Kwon
Young Eun
YE
Bae
Sung Jun
SJ
Kim
Myungjin
M
Seol
Jae Hong
JH
D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000502:physiology*; D009369:Neoplasms / Q000201:enzymology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C100023:HLTF protein, human; D009363:Neoplasm Proteins; D017395:Plasminogen Activator Inhibitor 1; D000075223:Poly-ADP-Ribose Binding Proteins; C051321:SERPINE1 protein, human; D014157:Transcription Factors; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex