Nucleic Acids Research Advance Access published online on November 27, 2006
Nucleic Acids Research, doi:10.1093/nar/gkl861
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Molecular Biology |
Transcriptional regulation of the cyclin-dependent kinase inhibitor 1A (p21) gene by NFI in proliferating human cells
Service of Genetics, Department of Pediatrics Université de Sherbrooke, Sherbrooke, Québec, Canada 1 Oncology and Molecular Endocrinology Research Center Centre Hospitalier Universitaire de Québec and Laval University Québec, Québec, Canada 2 Unit of ophthalmology, CHUL, Centre Hospitalier Universitaire de Québec and Laval University Québec, Québec, Canada
*To whom Correspondence should be addressed. Tel: +418 654 2296; Fax: +418 654 2761; Email: sylvain.guerin{at}crchul.ulaval.ca
Received September 6, 2006. Revised September 29, 2006. Accepted October 3, 2006.
The cyclin-dependent kinase inhibitor 1A (CDKN1A), also known as p21 (WAF1/CIP1) modulates cell cycle, apoptosis, senescence and differentiation via specific protein–protein interactions with the cyclins, cyclin-dependent kinase (Cdk), and many others. Expression of the p21 gene is mainly regulated at the transcriptional level. By conducting both ligation-mediated PCR (LMPCR) and chromatin immunoprecipitation (ChIP) in vivo, we identified a functional target site for the transcription factor, nuclear factor I (NFI), in the basal promoter from the p21 gene. Transfection of recombinant constructs bearing mutations in the p21 NFI site demonstrated that NFI acts as a repressor of p21 gene expression in various types of cultured cells. Inhibition of NFI in human skin fibroblasts through RNAi considerably increased p21 promoter activity suggesting that NFI is a key repressor of p21 transcription. Over-expression of each of the four NFI isoforms in HCT116 cells established that each of them contribute to various extend to the repression of the p21 gene. Most of all, over-expression of NFI-B in doxorubicin, growth-arrested HCT116 increased the proportion of cells in the S-phase of the cell cycle whereas NFI-A and NFI-X reduced it, thereby establishing a role for NFI in the cell cycle dependent expression of p21.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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