The Bmi-1 polycomb group gene in skin cancer: regulation of function by (−)–epigallocatechin-3-gallate

Extract

The PcG genes encode a family of evolutionarily conserved regulators that were discovered in Drosophila as repressors of Homoeotic gene expression. Homeotic genes are required to establish body segmentation patterns during development. In mammalian systems, PcG proteins regulate genes involved in development and differentiation, via epigenetic (e.g., chromatin modification) mechanisms. They are intimately involved as silencers of gene expression during cell lineage determination, and they play an important role in promoting cell survival. Proteins encoded by PcG genes comprise two protein complexes that act coordinately to regulate gene expression – the Bmi-1 complex and the Eed complex. The Bmi-1 complex includes Bmi-1, Mel-18, Mph1/Rae28, M33, Scmh1, Ring1A, and Ring1B, while the Eed complex includes Eed, EzH1, and EzH2. The first step in gene silencing is mediated by the Eed complex. Eed-containing complexes modify chromatin by recruiting histone deacetylase, which leads to local chromatin deacetylation. The Eed complex also catalyzes the methylation of Lys₂₇ of histone H3. In the second step, the Bmi-1 complex binds to the methylated Lys₂₇ of histone H3 and then catalyzes the ubiquitinylation of histone H2A. This cooperation between the Eed and Bmi-1 complexes leads to silencing of gene expression. The Bmi-1 complex appears to remain anchored to the chromatin after these events are completed. The Bmi-1 PcG protein has a particularly important role in gene silencing due to its ability to enhance the rate and extent of histone ubiquitinylation. This is accomplished through activation of Ring 1B, a ubiquitin ligase (and PcG protein) present in the Bmi-1 complex.^1,2