G1/S-Specific Transcription

Stable Identifier
Homo sapiens
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The E2F family of transcription factors regulate the transition from the G1 to the S phase in the cell cycle. E2F activity is regulated by members of the retinoblastoma protein (pRb) family, resulting in the tight control of the expression of E2F-responsive genes. Phosphorylation of pRb by cyclin D:CDK complexes releases pRb from E2F, inducing E2F-targeted genes such as cyclin E.

E2F1 binds to E2F binding sites on the genome activating the synthesis of the target proteins. For annotation purposes, the reactions regulated by E2F1 are grouped under this pathway and information about the target genes alone are displayed for annotation purposes.
Cellular targets for activation by E2F1 include thymidylate synthase (TYMS) (DeGregori et al. 1995), Rir2 (RRM2) (DeGregori et al. 1995, Giangrande et al. 2004), Dihydrofolate reductase (DHFR) (DeGregori et al. 1995, Wells et al. 1997, Darbinian et al. 1999), Cdc2 (CDK1) (Furukawa et al. 1994, DeGregori et al. 1995, Zhu et al. 2004), Cyclin A1 (CCNA1) (DeGregori et al. 1995, Liu et al. 1998), CDC6 (DeGregori et al. 1995, Yan et al. 1998; Ohtani et al. 1998), CDT1 (Yoshida and Inoue 2004), CDC45 (Arata et al. 2000), Cyclin E (CCNE1) (Ohtani et al. 1995), Emi1 (FBXO5) (Hsu et al. 2002), and ORC1 (Ohtani et al. 1996, Ohtani et al. 1998). The activation of TK1 (Dnk1) (Dou et al. 1994, DeGregori et al. 1995, Giangrande et al. 2004) and CDC25A (DeGregori et al. 1995, Vigo et al. 1999) by E2F1 is conserved in Drosophila (Duronio and O'Farrell 1994, Reis and Edgar 2004).
RRM2 protein is involved in dNTP level regulation and activation of this enzyme results in higher levels of dNTPs in anticipation of S phase. E2F activation of RRM2 has been shown also in Drosophila by Duronio and O'Farrell (1994). E2F1 activation of CDC45 is shown in mouse cells by using human E2F1 construct (Arata et al. 2000). Cyclin E is also transcriptionally regulated by E2F1. Cyclin E protein plays important role in the transition of G1 in S phase by associating with CDK2 (Ohtani et al. 1996). E2F1-mediated activation of PCNA has been demonstrated in Drosophila (Duronio and O'Farrell 1994) and in some human cells by using recombinant adenovirus constructs (DeGregori et al. 1995). E2F1-mediated activation of the DNA polymerase alpha subunit p180 (POLA1) has been demonstrated in some human cells. It has also been demonstrated in Drosophila by Ohtani and Nevins (1994). It has been observed in Drosophila that E2F1 induced expression of Orc1 stimulates ORC1 6 complex formation and binding to the origin of replication (Asano and Wharton 1999). ORC1 6 recruit CDC6 and CDT1 that are required to recruit the MCM2 7 replication helicases. E2F1 regulation incorporates a feedback mechanism wherein Geminin (GMNN) can inhibit MCM2 7 recruitment of ORC1 6 complex by interacting with CDC6/CDT1. The activation of CDC25A and TK1 (Dnk1) by E2F1 has been inferred from similar events in Drosophila (Duronio RJ and O'Farrell 1994; Reis and Edgar 2004). E2F1 activates string (CDC25) that in turn activates the complex of Cyclin B and CDK1. A similar phenomenon has been observed in mouse NIH 3T3 cells and in Rat1 cells.

Literature References
PubMed ID Title Journal Year
10454584 CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase

Vigo, E, Muller, H, Prosperini, E, Hateboer, G, Cartwright, P, Moroni, MC, Helin, K

Mol Cell Biol 1999
8288595 G1/S-regulated E2F-containing protein complexes bind to the mouse thymidine kinase gene promoter

Dou, QP, Zhao, S, Levin, AH, Wang, J, Helin, K, Pardee, AB

J. Biol. Chem. 1994
10597240 Association of Pur alpha and E2F-1 suppresses transcriptional activity of E2F-1

Darbinian, N, Gallia, GL, Kundu, M, Shcherbik, N, Tretiakova, A, Giordano, A, Khalili, K

Oncogene 1999
10692433 Cdk2-dependent and -independent pathways in E2F-mediated S phase induction

Arata, Y, Fujita, M, Ohtani, K, Kijima, S, Kato, JY

J Biol Chem 2000
7623816 Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes

DeGregori, J, Kowalik, T, Nevins, JR

Mol Cell Biol 1995
9520412 Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells.

Yan, Z, DeGregori, J, Shohet, R, Leone, G, Stillman, B, Nevins, JR, Williams, RS

Proc Natl Acad Sci U S A 1998
15014447 Combinatorial gene control involving E2F and E Box family members

Giangrande, PH, Zhu, W, Rempel, RE, Laakso, N, Nevins, JR

EMBO J. 2004
15084262 Negative regulation of dE2F1 by cyclin-dependent kinases controls cell cycle timing

Reis, T, Edgar, BA

Cell 2004
7929342 The role of cellular transcription factor E2F in the regulation of cdc2 mRNA expression and cell cycle control of human hematopoietic cells

Furukawa, Y, Terui, Y, Sakoe, K, Ohta, M, Saito, M

J. Biol. Chem. 1994
15510213 E2Fs link the control of G1/S and G2/M transcription

Zhu, W, Giangrande, PH, Nevins, JR

EMBO J. 2004
11988738 E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1)

Hsu, JY, Reimann, JD, Sorensen, CS, Lukas, J, Jackson, PK

Nat Cell Biol 2002
9662327 A new model of cell cycle-regulated transcription: repression of the cyclin A promoter by CDF-1 and anti-repression by E2F

Liu, N, Lucibello, FC, Engeland, K, Müller, R

Oncogene 1998
8050359 Developmental control of a G1-S transcriptional program in Drosophila

Duronio, RJ, O'Farrell, PH

Development 1994
9020173 Accumulation of E2F-4.DP-1 DNA binding complexes correlates with induction of dhfr gene expression during the G1 to S phase transition

Wells, JM, Illenye, S, Magae, J, Wu, CL, Heintz, NH

J. Biol. Chem. 1997
14990995 Regulation of Geminin and Cdt1 expression by E2F transcription factors

Yoshida, K, Inoue, I

Oncogene 2004
10228158 E2F mediates developmental and cell cycle regulation of ORC1 in Drosophila

Asano, M, Wharton, RP

EMBO J 1999
8618861 Regulation of the cyclin E gene by transcription factor E2F1

Ohtani, K, DeGregori, J, Nevins, JR

Proc Natl Acad Sci U S A 1995
8114698 Functional properties of a Drosophila homolog of the E2F1 gene

Ohtani, K, Nevins, JR

Mol Cell Biol 1994
8943353 Expression of the HsOrc1 gene, a human ORC1 homolog, is regulated by cell proliferation via the E2F transcription factor

Ohtani, K, DeGregori, J, Leone, G, Herendeen, DR, Kelly, TJ, Nevins, JR

Mol Cell Biol 1996
9778043 Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F.

Ohtani, K, Tsujimoto, A, Ikeda, M, Nakamura, M

Oncogene 1998
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