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Induction and Analysis of Epithelial to Mesenchymal Transition
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Direct repression of cyclin D1 by SIP1 attenuates cell cycle progression in cells undergoing an epithelial

Jakob Mejlvang1, Marina Kriajevska, Cindy Vandewalle

  • 1Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 9HN, United Kingdom.

Molecular Biology of the Cell
|September 15, 2007
PubMed

Insights

SIP1 transcription factor triggers cell invasion by inhibiting cyclin D1 expression, leading to Rb hypophosphorylation and G1 cell cycle arrest. This invasion mechanism is independent of cell cycle progression, suggesting a broader role in epithelial-mesenchymal transitions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Epithelial-mesenchymal transition (EMT) is crucial in development and cancer.
  • Zinc finger transcription factors, including Snail/Slug and ZEB-1/SIP1, regulate EMT.
  • SIP1 (SMARCC1-interacting protein 1) is a key regulator of EMT.

Purpose of the Study:

  • To investigate SIP1-regulated mesenchymal conversion in A431 epidermoid cells.
  • To elucidate the role of SIP1 in regulating cell cycle progression and invasion.
  • To determine the necessity and sufficiency of cyclin D1 repression in SIP1-induced cellular changes.

Main Methods:

  • Studied SIP1-regulated mesenchymal conversion in A431 cells.
  • Analyzed SIP1's effect on cyclin D1 expression and Rb protein phosphorylation.
  • Investigated SIP1 binding to the cyclin D1 gene promoter using reporter assays.
  • Utilized exogenous cyclin D1 expression and RNA interference to assess its role.
  • Compared SIP1-induced EMT with EMT induced by dominant-negative E-cadherin.

Main Results:

  • SIP1 induced an invasive phenotype and inhibited cyclin D1 expression.
  • SIP1 directly bound to the cyclin D1 promoter, repressing its transcription.
  • SIP1-mediated repression of cyclin D1 caused Rb hypophosphorylation and G1 cell cycle arrest.
  • SIP1-induced invasion was independent of G1/S phase progression attenuation.
  • EMT induced by dominant-negative E-cadherin did not affect the cell cycle.

Conclusions:

  • SIP1-induced repression of cyclin D1 is necessary and sufficient for Rb hypophosphorylation and G1 arrest.
  • SIP1-driven cell invasion is independent of cell cycle progression.
  • Impaired G1/S phase progression is a common feature of EMT induced by Snail/Slug and ZEB-1/SIP1 family transcription factors.

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