The Rb/chromatin connection and epigenetic control: opinion

Abstract

The balance between cell di erentiation and proliferation is regulated at the transcriptional level. In the cell cycle, the transition from G1 to S phase (G1/S transition) is of paramount importance in this regard. Indeed, it is only before this point that cells can be oriented toward the di erentiation pathway: beyond, cells progress into the cycle in an autonomous manner. The G1/S transition is orchestrated by the transcription factor E2F. E2F controls the expression of a group of checkpoint genes whose products are required either for the G1-to-S transition itself or for DNA replication (e.g. DNA polymerase a). E2F activity is repressed in growth-arrested cells and in early G1, and is activated at mid-to-late G1. E2F is controlled by the retinoblastoma tumor suppressor protein Rb. Rb represses E2F mainly by recruiting chromatin remodeling factors (histone deacetylases and SWI/SNF complexes), the DNA methyltransferase DNMT1, and a histone methyltransferase. This review will focus on the molecular mechanisms of E2F repression by Rb during the cell cycle and during cell-cycle exit by di erentiating cells. A model in which Rb irreversibly represses E2F-regulated genes in di erentiated cells by an epigenetic mechanism linked to heterochromatin, and involving histone H3 and promoter DNA methylation, is discussed. Oncogene (2001) 20, 3128 ± 3133.

Inhibitory Activity of a Heterochromatin-associated Serpin (MENT) against Papain-like Cysteine Proteinases Affects Chromatin Structure and Blocks Cell Proliferation

“…and several other cell lines of a cathepsin L-like proteinase, SPase, whose activity correlated with degradation of underphosphorylated Rb protein (39), a factor that plays a pivotal role in regulating the cell cycle (40,41).…”

E2F Proteins Regulate MYCN Expression in Neuroblastomas

“…E2F proteins can repress target genes by associating with pocket proteins and recruiting a variety of co-repressor complexes (38). To test whether pocket proteins are bound to the MYCN promoter in undifferentiated or differentiated LA-N-5 cells and to exclude the possibility that masking of the antibody epitopes on the E2F proteins by associated pocket proteins in RA-treated cells prevented their detection in the ChIP assay, we performed another chromatin immunoprecipitation with a panel of pocket-protein-specific antibodies, which have previously been shown to detect repressive E2F complexes in ChIP assays (33).…”

Chromatin remodeling: why it is important in cancer

“…The p16 and Rb genes are also often silenced by DNA methylation. Rb functions by the recruitment of the human homologs of the SWI/SNF enzymes BRG1 (Zhang and Dean, 2001), histone deacetylase (Ferreira et al, 2001) and DNA methyltransferase (Robertson, 2001). Thus a key checkpoint protein depends on chromatin remodeling to silence genes that would otherwise drive continued cell proliferation.…”