E2F target genes: unraveling the biology

doi:10.1016/j.tibs.2004.06.006

Trends in Biochemical Sciences

Volume 29, Issue 8, 1 August 2004, Pages 409-417

https://doi.org/10.1016/j.tibs.2004.06.006 Get rights and content

The E2F transcription factors are downstream effectors of the retinoblastoma protein (pRB) pathway and are required for the timely regulation of numerous genes essential for DNA replication and cell cycle progression. Several laboratories have used genome-wide approaches to discover novel target genes of E2F, leading to the identification of several hundred such genes that are involved not only in DNA replication and cell cycle progression, but also in DNA damage repair, apoptosis, differentiation and development. These new findings greatly enrich our understanding of how E2F controls transcription and cellular homeostasis.

Section snippets

Identification of E2F target genes

The discovery of its connection with pRB, and therefore cancer, greatly increased efforts aimed towards understanding how E2F controls cell proliferation. When the first E2F family members were identified, they were indeed shown to be capable of transactivating E2F-responsive promoters and to push immortalized quiescent cells into the S phase of the cell cycle 11, 12, 13. These results were satisfying, because they showed that the ectopic expression of key interactors of pRB was sufficient to

How does E2F regulate genes outside G1/S?

CCND1 and MYC mRNAs accumulate in early G1 upon the stimulation of quiescent cells to enter the cell cycle, whereas CDC2 and CCNA2 mRNAs accumulate later in S/G2 (Table 1, Table 1), suggesting that different mechanisms of regulation must exist for these genes. The best-studied example of an E2F target gene that accumulates in S phase is CCNA2 [23]. In non-growing cells, the pocket proteins p107 and p130 form complexes with E2F4 or E2F5 on the CCNA2 promoter, which coincides with gene repression

Can E2F1–E2F3 execute pocket-protein-independent gene repression?

Genome-wide expression approaches have pinpointed an unexpectedly large number of genes whose expression is repressed upon overexpression of E2F 16, 17, 18, 32. For example, Müller et al. [16] identified several hundred genes that were repressed upon overexpression of E2F1–E2F3. The regulation of six of these genes (PAI-1, CTGF, EPLIN, TGFB2, BCL3 and INHBA) was subsequently shown to be reduced even in the absence of protein synthesis. This suggests that E2F1–E2F3 can function as direct

Does E2F control negative growth regulators to fine-tune cell cycle progression?

Of the newly identified E2F target genes, several encode negative regulators of cell proliferation (Table 1, Table 1). This might seem surprising, because E2F is best known for its role in regulating the transcription of genes that positively affect cell cycle progression. CDKN2C (encoding p18), CDKN2D (p19), CDKN1C (p57), E2F7, RB1 (pRB) and RBL1 (p107) are upregulated by E2F during S phase, yet these genes are known to regulate cell growth negatively when overexpressed 36, 37, 38, 39. Their

A role for E2F in the DNA damage response?

The discovery that DNA damage results in ATM-mediated phosphorylation of E2F1 and its subsequent stabilization has suggested that E2F might have a role in mediating the DNA damage response [42]. Such a role is supported by the presence of many checkpoint (CHK1, TP53, ATM, BRCA1 and BRCA2) and DNA damage repair (RPA1–RPA3, RAD51, RAD54, MSH2–MSH6 and MLH1) genes among E2F targets (Table 1, Table 1). But checkpoint and DNA repair proteins have been also proposed to function in non-stressed cells

Is E2F involved in regulating apoptosis, development and differentiation?

Many newly identified E2F target genes have been found in diverse functional groups such as apoptosis, development and differentiation (Table 1, Table 1). Below, we discuss the potential role of E2F in some of these biological processes.

Perspectives and future directions

The E2F transcription factors are crucial for regulating cell cycle progression and tumorigenesis. Therefore, to understand these biological processes, we need to unravel the mechanisms by which these factors exert control. The nature and function of the several hundred E2F target genes identified by genome-wide approaches have already disclosed, and will continue to open up, many directions in the field of E2F biology. Several potential pitfalls in the recently developed genome-wide approaches

Acknowledgements

We thank Claire Attwooll, Emmanuelle Trinh, Eros Lazzerini Denchi and Luisa Di Stefano for critically reading the manuscript and helpful discussions. This work was supported by grants from the Association for International Cancer Research, Associazione Italiana per la Ricerca sul Cancro (AIRC), Fondazione Italiana per la Ricerca sul Cancro (FIRC), The European Union Fifth Framework Program, The Italian Health Ministry, and the Danish Ministry of Research.

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Trends in Biochemical Sciences

E2F target genes: unraveling the biology

Section snippets

Identification of E2F target genes

How does E2F regulate genes outside G1/S?

Can E2F1–E2F3 execute pocket-protein-independent gene repression?

Does E2F control negative growth regulators to fine-tune cell cycle progression?

A role for E2F in the DNA damage response?

Is E2F involved in regulating apoptosis, development and differentiation?

Perspectives and future directions

Acknowledgements

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J. Biol. Chem.

Cell

Cancer Cell

FEBS Lett.

Cell

Curr. Opin. Cell Biol.

Cell

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

Dev. Cell

The Rb/E2F pathway and cancer

Hum. Mol. Genet.

The E2F transcription factors: key regulators of cell proliferation

Biochim. Biophys. Acta

Nuclear factor E2F mediates basic transcription and trans-activation by E1a of the human MYC promoter

Genes Dev.

Transcription factor E2F is required for efficient expression of the hamster dihydrofolate reductase gene in vitro and in vivo

Mol. Cell. Biol.

Sibling rivalry in the E2F family

Nat. Rev. Mol. Cell Biol.

The Rb/chromatin connection and epigenetic control: opinion

Oncogene

Expression of transcription factor E2F1 induces quiescent cells to enter S phase

Nature

Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression

Mol. Cell. Biol.

Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis

Proc. Natl. Acad. Sci. U. S. A.

E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis

Oncogene

Deregulated expression of E2F family members induces S-phase entry and overcomes p16^INK4A-mediated growth suppression