期刊
BIOCHEMICAL JOURNAL
卷 436, 期 -, 页码 133-143出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20101798
关键词
adhesion; cell cycle; proliferation; S-phase kinase-associated protein 2 (Skp2); selenocysteine tRNA gene transcription-activating factor (STAF); ZNF76; ZNF143
资金
- British Heart Foundation [PG/08/004/24339, CH95/001]
- NIHR (National Institute of Health Research) Bristol Biomedical Research Unit in Cardiovascular Medicine
Cell adhesion is essential for cell cycle progression in most normal cells. Loss of adhesion dependence is a hallmark of cellular transformation. The F-box protein Skp2 (S-phase kinase-associated protein 2) controls G(1)-S-phase progression and is subject to adhesion-dependent transcriptional regulation, although the mechanisms are poorly understood. We identify two cross-species conserved binding elements for the STAF (selenocysteine tRNA gene transcription-activating factor) in the Skp2 promoter that are essential for Skp2 promoter activity. Endogenous STAF specifically binds these elements in EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation) analysis. STAF is sufficient and necessary for Skp2 promoter activity since exogenous STAF activates promoter activity and expression and STAF siRNA (small interfering RNA) inhibits Skp2 promoter activity, mRNA and protein expression and cell proliferation. Furthermore, ectopic Skp2 expression completely reverses the inhibitory effects of STAF silencing on proliferation. Importantly, STAF expression and binding to the Skp2 promoter is adhesion-dependent and associated with adhesion-dependent Skp2 expression in non-transformed cells. Ectopic STAF rescues Skp2 expression in suspension cells. Taken together, these results demonstrate that STAF is essential and sufficient for Skp2 promoter activity and plays a role in the adhesion-dependent expression of Skp2 and ultimately cell proliferation.
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