Network calisthenics

Abstract

Stimulation of quiescent mammalian cells with mitogens induces an abrupt increase in E2F1-3 expression just prior to the onset of DNA synthesis, followed by a rapid decline as replication ceases. This temporal adaptation in E2F facilitates a transient pattern of gene expression that reflects the ordered nature of DNA replication. The challenge to understand how E2F dynamics coordinate molecular events required for high-fidelity DNA replication has great biological implications. Indeed, precocious, prolonged, elevated or reduced accumulation of E2F can generate replication stress that culminates in either arrest or death. Accordingly, temporal characteristics of E2F are regulated by several network modules that include feedforward and autoregulatory loops. In this review, we discuss how these network modules contribute to "shaping" E2F dynamics in the context of mammalian cell cycle entry.

p53 can repress transcription of cell cycle genes through a p21WAF1/CIP1-dependent switch from MMB to DREAM protein complex binding at CHR promoter elements

“…While E2F1–3 had been linked to activating functions early in the cell cycle, E2F4 in particular had been implicated to function as a component of the DREAM repressor complex 23 , 24 , 42 . The fact that E2F4 and DP1 are part of the complex together with results from ChIP-chip experiments suggested at the time that DREAM binds through E2F4/DP1 to E2F sites in the promoters of cell cycle genes 23 .…”

Post-mitotic role of the cell cycle machinery

“…While the center of the process is the duplication of the cell’s genome, DNA replication must proceed in a cellular context that includes the proper regulation of other cellular events including metabolism, transcription, translation and mitochondrial biogenesis, as well as chromatin condensation, spindle formation and ultimately cytokinesis. Many solid reviews are written each year on this topic and the interested reader is referred to them for more details (1–5); a brief overview will suffice here.…”

Analysis of Transcriptional Regulation of the Human miR-17-92 Cluster; Evidence for Involvement of Pim-1

“…For future investigations, other cell lines will be tested, particularly ones that express c-Myc, but not Pim-1. Clearly, decreases in pri-miR-17-92 levels upon c-Myc, E2F3 and/or Pim-1 knockdown (Figure 3) may include indirect effects, e.g., originating from inhibition of cell proliferation (Pim-1), changes in the kinetics of pri-miR-17-92 processing, global changes in transcriptional networks (E2F3, c-Myc) or mutual transactivation (E2F3 and c-Myc) [33–35]. Further complication may arise from the fact that miR-17-5p and miR-20a of the cluster are negative regulators of E2F1-3 mRNAs [10,18].…”

“…Box E1, immediately downstream of host gene promoter’s TSS, was shown by deletion analysis to be inhibitory, which correlates with c-Myc forming heterodimers with MXI or MNT at this site to repress transcription [20]. Thus, host gene promoter activity may even somewhat increase under conditions of a c-Myc knockdown, although such an effect could, in turn, be neutralized by reduced c-Myc-mediated transactivation of E2F [35]. ChIP-Seq data for K562 and HeLa-S3 cells revealed the by far highest c-Myc occupancy at site E3 (little at E2 and E4), where c-Myc forms heterodimers with MAX to activate transcription [20].…”