Direct Repression of Cyclin D1 by SIP1 Attenuates Cell Cycle Progression in Cells Undergoing an Epithelial Mesenchymal Transition
- 1 November 2007
- journal article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 18 (11), 4615-4624
- https://doi.org/10.1091/mbc.e07-05-0406
Abstract
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.Keywords
This publication has 57 references indexed in Scilit:
- The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarityOncogene, 2007
- Characterization of E-cadherin-dependent and -independent events in a new model of c-Fos-mediated epithelial–mesenchymal transitionExperimental Cell Research, 2007
- Snail family genes are required for left–right asymmetry determination, but not neural crest formation, in miceProceedings of the National Academy of Sciences, 2006
- Cyclin D1: polymorphism, aberrant splicing and cancer riskOncogene, 2006
- Integrin-dependent signal transduction regulating cyclin D1 expression and G1 phase cell cycle progressionCancer and Metastasis Reviews, 2005
- The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulationJournal of Cell Science, 2004
- Correlation of Snail expression with histological grade and lymph node status in breast carcinomasOncogene, 2002
- The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expressionNature, 2000
- The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cellsNature, 2000
- The slug gene is not essential for mesoderm or neural crest development in miceDevelopmental Biology, 1998