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Transcriptional Regulation of Cyclin A2 by RASSF1A through the Enhanced Binding of p120^E4F to the Cyclin A2 Promoter

¹ Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom and ² Department of Cell and Cancer Biology, National Cancer Institute, Rockville, Maryland

Requests for reprints: Farida Latif, Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44-121-627-2741; Fax: 44-121-627-2618; E-mail: flatif{at}hgmp.mrc.ac.uk.

Recent advances in the study of RASSF1A, the candidate tumor suppressor gene, indicate a possible role of RASSF1A in cell cycle regulation; however, very little is known regarding molecular mechanisms underlying this control. Using small interfering RNA to knockdown endogenous RASSF1A in the breast tumor cell line HB2 and in the cervical cancer cell line HeLa, we identify that a key player in cell cycle progression, cyclin A2, is concomitantly increased at both protein and mRNA levels. In A549 clones stably expressing RASSF1A, cyclin A2 levels were diminished compared with vector control. A known transcriptional regulator of cyclin A2, p120^E4F (a repressor of cyclin A2), has been shown previously by our group to interact with RASSF1A. We show that levels of p120^E4F are not affected by RASSF1A small interfering RNA in HB2 and HeLa cells. However, electrophoretic mobility shift assays indicate that knockdown of endogenous RASSF1A in HB2 and HeLa cells leads to a reduction in the binding capacity of p120^E4F to the cyclin A2 promoter, whereas in the A549 clone stably expressing RASSF1A the binding capacity is increased. These data are further corroborated in vitro by the luciferase assay and in vivo by chromatin immunoprecipitation experiments. Together, these data identify the cyclin A2 gene as a cellular target for RASSF1A through p120^E4F and for the first time suggest a transcriptional mechanism for RASSF1A-dependent cell cycle regulation.

Key Words: RASSF1A • p120^E4F • Cyclin A2 • transcriptional regulation • RNAi

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