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Vol. 18, Issue 11, 4615-4624, November 2007

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Direct Repression of Cyclin D1 by SIP1 Attenuates Cell Cycle Progression in Cells Undergoing an Epithelial Mesenchymal Transition

Jakob Mejlvang^*, Marina Kriajevska^*, Cindy Vandewalle, Tatyana Chernova, A. Emre Sayan^*, Geert Berx, J. Kilian Mellon^*, and Eugene Tulchinsky^*

*Department of Cancer Studies and Molecular Medicine and Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom; and Unit of Molecular and Cellular Oncology, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology-Ghent University, BE-9052 Gent, Belgium

Submitted May 3, 2007; Revised August 27, 2007; Accepted September 4, 2007
Monitoring Editor: Ben Margolis

Zinc finger transcription factors of the Snail/Slug and ZEB-1/SIP1 families control epithelial-mesenchymal transitions in development in cancer. Here, we studied SIP1-regulated mesenchymal conversion of epidermoid A431 cells. We found that concomitant with inducing invasive phenotype, SIP1 inhibited expression of cyclin D1 and induced hypophosphorylation of the Rb tumor suppressor protein. Repression of cyclin D1 was caused by direct binding of SIP1 to three sequence elements in the cyclin D1 gene promoter. By expressing exogenous cyclin D1 in A431/SIP1 cells and using RNA interference, we demonstrated that the repression of cyclin D1 gene by SIP1 was necessary and sufficient for Rb hypophosphorylation and accumulation of cells in G1 phase. A431 cells expressing SIP1 along with exogenous cyclin D1 were highly invasive, indicating that SIP1-regulated invasion is independent of attenuation of G1/S progression. However, in another epithelial-mesenchymal transition model, gradual mesenchymal conversion of A431 cells induced by a dominant negative mutant of E-cadherin produced no effect on the cell cycle. We suggest that impaired G1/S phase progression is a general feature of cells that have undergone EMT induced by transcription factors of the Snail/Slug and ZEB-1/SIP1 families.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Eugene Tulchinsky (et32{at}le.ac.uk)

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