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Sibling rivalry in the E2F family

Nature Reviews Molecular Cell Biology volume 3, pages 11–20 (2002)Cite this article

Abstract

The E2F transcription factor family determines whether or not a cell will divide by controlling the expression of key cell-cycle regulators. The individual E2Fs can be divided into distinct subgroups that act in direct opposition to one another to promote either cellular proliferation or cell-cycle exit and terminal differentiation. What is the underlying molecular basis of this 'push-me–pull-you' regulation, and what are its biological consequences?

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Figure 1: General mechanisms that control the repressive activity of E2F.
Figure 2: Structural comparison of the E2F subgroups.
Figure 3: Cell-cycle regulation of individual E2F complexes.
Figure 4: The threshold model of the activating E2Fs.

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Authors and Affiliations

  1. Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Jeffrey M. Trimarchi & Jacqueline A. Lees

Authors
  1. Jeffrey M. Trimarchi
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Correspondence to Jacqueline A. Lees.

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DATABASES

Encyclopedia of Life Sciences:

cell division cycle

nucleosome structures

 LocusLink:

ATR

B-myb

cdc2

CRM1

cyclin A2

cyclin E

dE2F2

DP1

E2f1

E2f2

E2f3

E2f4

E2f5

p16

p19ARF

p21

p27

p107

p130

pRB

RYBP

SUV39H2

thymidylate synthetase

 Swiss-Prot:

ATM

Bmi-1

CBFA1

Cdc2

Cdc6

Cdc25A

Cdk2

Cdk4

Cdk6

c-myc

cyclin A

cyclin D1

dE2F1

dihydrofolate reductase

E2F1

E2F2

E2F3

E2F4

E2F5

E2F6

HP1

Mre11

ORC1

p53

p73

PPAR-γ

SUV39H1

thymidine kinase

Glossary

CHECKPOINT PATHWAYS

The classic definition of a checkpoint pathway/protein is one that is not required for normal cell-cycle regulation but is essential for the ability of the cell to arrest in response to a stress condition. Frequently, this term is used less strictly to describe proteins that have a key role in cell-cycle-stress responses, regardless of their role in normal cell-cycle regulation.

p53

The p53 transcription factor is activated in response to various stress conditions, including DNA damage. It activates various target genes that trigger either apoptosis or cell-cycle arrest, depending on the cell type and the stress conditions. p53 is a tumour suppressor and it, or its upstream regulators, are disrupted in a large proportion of human tumours.

CHROMATIN-IMMUNOPRECIPITATION (ChIP) ASSAYS

ChIP assays can be used to monitor the association of DNA-binding proteins with specific promoters in vivo. Briefly, live cells are treated with crosslinking agents to tether the proteins to the DNA. The selected protein is then recovered by immunoprecipitation, the crosslinking is reversed and the co-precipitating DNA is screened for the enrichment of specific promoter fragments using the polymerase chain reaction (PCR).

TRANSFORMATION

Transformation is the process by which a primary cell becomes a tumour cell. It is generally characterized by a reduction in growth-factor dependence, a failure to arrest growth in response to contact inhibition, and the ability to grow in soft agar (that is, without attachment).

PRIMARY CELLS

Primary cells are cells that are derived from a living organism. They undergo a limited, predetermined number of cell divisions before arresting permanently in G0 — a process that is called cellular senescence.

p19ARF

The p19ARF gene (the human equivalent is called p14ARF) is expressed from the Ink4 locus and its coding sequence partially overlaps with that of p16INK4a. The p19ARF protein activates p53 by binding to Mdm2 (an E3 ubiquitin ligase) and prevents it from triggering p53 degradation.

THE NBS1/MRE11 COMPLEX

The Nbs1 gene was identified by virtue of its mutation in the inherited chromosome instability disorder Nijmegen breakage syndrome (NBS). Its protein product, Nibrin, forms a complex with the DNA-repair proteins Mre11 and Rad50. This complex seems to have an important role in recombinational DNA repair, replication and the activation of a DNA-damage induced S-phase checkpoint.

POLYCOMB COMPLEX

Polycomb (Pc) was identified as a dominant mutation in Drosophila that led to the presence of sex combs on the second and third legs of male flies instead of only the first leg. The Drosophila polycomb group (PcG) includes several genes that yield similar homeotic transformation phenotypes when mutated. Their protein products associate with one another to form at least two possible Polycomb complexes. These maintain the repression of hox gene expression, which is essential for embryonic patterning. The PcG also exists in mammals, but seems much more complex.

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Trimarchi, J., Lees, J. Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 3, 11–20 (2002). https://doi.org/10.1038/nrm714

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