* 600426

E2F TRANSCRIPTION FACTOR 2; E2F2


HGNC Approved Gene Symbol: E2F2

Cytogenetic location: 1p36.12     Genomic coordinates (GRCh38): 1:23,505,212-23,531,233 (from NCBI)


TEXT

See E2F1 (189971).


Cloning and Expression

Ivey-Hoyle et al. (1993) cloned a cDNA from a HeLa cell library using a probe containing the DNA-binding domain of E2F1. The cDNA, designated E2F2, has overall amino acid sequence similarity to E2F1 of 46%. The same cDNA and corresponding genomic region was cloned by Lees et al. (1993). Lees et al. (1993) also showed that expressed E2F2 bound to both the E2F DNA recognition sites and to the RB1 protein (614041).


Gene Function

MYC (190080) induces transcription of the E2F1, E2F2, and E2F3 (600427) genes. Using primary mouse embryo fibroblasts deleted for individual E2f genes, Leone et al. (2001) showed that MYC-induced S phase and apoptosis requires distinct E2F activities. The ability of Myc to induce S phase was impaired in the absence of either E2f2 or E2f3 but not E2f1 or E2f4 (600659). In contrast, the ability of Myc to induce apoptosis was markedly reduced in cells deleted for E2f1 but not E2f2 or E2f3. The authors proposed that the induction of specific E2F activities is an essential component in the MYC pathways that control cell proliferation and cell fate decisions.

The retinoblastoma tumor suppressor (Rb) pathway is believed to have a critical role in the control of cellular proliferation by regulating E2F activities. E2F1, E2F2, and E2F3 belong to a subclass of E2F factors thought to act as transcriptional activators important for progression through the G1/S transition. Wu et al. (2001) used a conditional gene targeting approach to demonstrate that combined loss of these 3 E2F factors severely affects E2F target expression and completely abolishes the ability of mouse embryonic fibroblasts to enter S phase, progress through mitosis, and proliferate. Loss of E2F function results in elevation of CIP1 (116899) protein, leading to a decrease in cyclin-dependent kinase activity and Rb phosphorylation. Wu et al. (2001) concluded that these findings suggested a function for this subclass of E2F transcriptional activators in a positive feedback loop, through downmodulation of CIP1, that leads to the inactivation of Rb-dependent repression and S phase entry. By targeting the entire subclass of E2F transcriptional activators, Wu et al. (2001) provided direct genetic evidence for their essential role in cell cycle progression, proliferation, and development. Wu et al. (2001) initially generated and interbred E2f1, E2f2, and E2f3 mutant mice, and found that although mice null for E2f1 and E2f2 were viable and developed to adulthood, mice null for E2f1 and E2f3 or E2f2 and E2f3 died early during embryonic development, at or just before embryonic day 9.5, pointing to a central role for E2F3 in mouse development.

Funke-Kaiser et al. (2003) identified 5 polymorphisms in the ECE1 gene (600423), a candidate for human blood pressure regulation, among a cohort of 704 European hypertensive patients. Electrophoretic mobility shift assays revealed the specific binding of E2F2 to ECE1b promoter sequences containing either allele of the C-338A polymorphism (600423.0002), with the -338A allele being associated with an increased affinity to E2F2 compared with -338C. The authors proposed a link between the cell cycle-associated E2F family and blood pressure regulation via a component of the endothelin system.

To address the function of E2F1, E2F2, and E2F3 in normal mammalian cells in vivo, Chen et al. (2009) focused on the mouse retina, which is a relatively simple central nervous system component that can be manipulated genetically without compromising viability and has provided considerable insight into development and cancer. The authors showed that unlike fibroblasts, E2f1-, E2f2-, and E2f3-null retinal progenitor cells or activated Muller glia can divide. Chen et al. (2009) attributed this effect to functional interchangeability with Mycn (164840). However, loss of activating E2fs caused downregulation of the p53 (191170) deacetylase Sirt1 (604479), p53 hyperacetylation, and elevated apoptosis, establishing a novel E2f-Sirt1-p53 survival axis in vivo. Chen et al. (2009) concluded that activating E2fs are not universally required for normal mammalian cell division, but have an unexpected prosurvival role in development.

Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles, Chong et al. (2009) examined the effects of E2f1, E2f2, and E2f3 triple deficiency in murine embryonic stem cells, embryos, and small intestines. They showed that in normal dividing progenitor cells, E2f1-3 function as transcriptional activators, but are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb (614041) as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f-responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. Chong et al. (2009) concluded that their work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.


Mapping

Lees et al. (1993) mapped the E2F2 gene to 1p36 by fluorescence in situ hybridization.


Animal Model

Iglesias et al. (2004) generated mice deficient in both E2f1 (189971) and E2f2. The mice developed nonautoimmune insulin-deficient diabetes and exocrine pancreatic dysfunction characterized by endocrine and exocrine cell dysplasia and a reduction in the number and size of acini and islets, which were replaced by ductal structures and adipose tissue. Mutant pancreatic cells exhibited increased rates of DNA replication but also of apoptosis, resulting in severe pancreatic atrophy. The expression of genes involved in DNA replication and cell cycle control was upregulated in the E2f1/E2f2 compound mutant pancreas. Iglesias et al. (2004) suggested that E2F1/E2F2 activity negatively controls growth of mature pancreatic cells and is necessary for the maintenance of differentiated pancreatic phenotypes in the adult.


REFERENCES

  1. Chen, D., Pacal, M., Wenzel, P., Knoepfler, P. S., Leone, G., Bremner, R. Division and apoptosis of E2f-deficient retinal progenitors. Nature 462: 925-929, 2009. [PubMed: 20016601, images, related citations] [Full Text]

  2. Chong, J.-L., Wenzel, P. L., Saenz-Robles, M. T., Nair, V., Ferrey, A., Hagan, J. P., Gomez, Y. M., Sharma, N., Chen, H.-Z., Ouseph, M., Wang, S.-H., Trikha, P., and 10 others. E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature 462: 930-934, 2009. [PubMed: 20016602, images, related citations] [Full Text]

  3. Funke-Kaiser, H., Reichenberger, F., Kopke, K., Herrmann, S.-M., Pfeifer, J., Orzechowski, H.-D., Zidek, W., Paul, M., Brand, E. Differential binding of transcription factor E2F-2 to the endothelin-converting enzyme-1b promoter affects blood pressure regulation. Hum. Molec. Genet. 12: 423-433, 2003. Note: Erratum: Hum. Molec. Genet. 12: 947 only, 2003. [PubMed: 12566389, related citations] [Full Text]

  4. Iglesias, A., Murga, M., Laresgoiti, U., Skoudy, A., Bernales, I., Fullaondo, A., Moreno, B., Lloreta, J., Field, S. J., Real, F. X., Zubiaga, A. M. Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice. J. Clin. Invest. 113: 1398-1407, 2004. [PubMed: 15146237, images, related citations] [Full Text]

  5. Ivey-Hoyle, M., Conroy, R., Huber, H. E., Goodhart, P. J., Oliff, A., Heimbrook, D. C. Cloning and characterization of E2F-2, a novel protein with the biochemical properties of transcription factor E2F. Molec. Cell. Biol. 13: 7802-7812, 1993. [PubMed: 8246995, related citations] [Full Text]

  6. Lees, J. A., Saito, M., Vidal, M., Valentine, M., Look, T., Harlow, E., Dyson, N., Helin, K. The retinoblastoma protein binds to a family of E2F transcription factors. Molec. Cell. Biol. 13: 7813-7825, 1993. [PubMed: 8246996, related citations] [Full Text]

  7. Leone, G., Sears, R., Huang, E., Rempel, R., Nuckolls, F., Park, C.-H., Giangrande, P., Wu, L., Saavedra, H. I., Field, S. J., Thompson, M. A., Yang, H., Fujiwara, Y., Greenberg, M. E., Orkin, S., Smith, C., Nevins, J. R. Myc requires distinct E2F activities to induce S phase and apoptosis. Molec. Cell 8: 105-113, 2001. [PubMed: 11511364, related citations] [Full Text]

  8. Wu, L., Timmers, C., Maiti, B., Saavedra, H. I., Sang, L., Chong, G. T., Nuckolls, F., Giangrande, P., Wright, F. A., Field, S. J., Greenberg, M. E., Orkin, S., Nevins, J. R., Robinson, M. L., Leone, G. The E2F1-3 transcription factors are essential for cellular proliferation. Nature 414: 457-462, 2001. [PubMed: 11719808, related citations] [Full Text]


Ada Hamosh - updated : 1/6/2010
George E. Tiller - updated : 1/6/2005
Marla J. F. O'Neill - updated : 6/17/2004
Ada Hamosh - updated : 11/26/2001
Stylianos E. Antonarakis - updated : 8/3/2001
Alan F. Scott - updated : 9/20/1995
Creation Date:
Victor A. McKusick : 2/22/1995
terry : 04/01/2013
carol : 6/17/2011
alopez : 1/15/2010
terry : 1/6/2010
alopez : 9/26/2008
terry : 9/24/2008
alopez : 1/6/2005
carol : 6/17/2004
terry : 6/17/2004
alopez : 11/26/2001
alopez : 11/26/2001
terry : 11/26/2001
mgross : 8/3/2001
mark : 4/7/1996
carol : 2/22/1995

* 600426

E2F TRANSCRIPTION FACTOR 2; E2F2


HGNC Approved Gene Symbol: E2F2

Cytogenetic location: 1p36.12     Genomic coordinates (GRCh38): 1:23,505,212-23,531,233 (from NCBI)


TEXT

See E2F1 (189971).


Cloning and Expression

Ivey-Hoyle et al. (1993) cloned a cDNA from a HeLa cell library using a probe containing the DNA-binding domain of E2F1. The cDNA, designated E2F2, has overall amino acid sequence similarity to E2F1 of 46%. The same cDNA and corresponding genomic region was cloned by Lees et al. (1993). Lees et al. (1993) also showed that expressed E2F2 bound to both the E2F DNA recognition sites and to the RB1 protein (614041).


Gene Function

MYC (190080) induces transcription of the E2F1, E2F2, and E2F3 (600427) genes. Using primary mouse embryo fibroblasts deleted for individual E2f genes, Leone et al. (2001) showed that MYC-induced S phase and apoptosis requires distinct E2F activities. The ability of Myc to induce S phase was impaired in the absence of either E2f2 or E2f3 but not E2f1 or E2f4 (600659). In contrast, the ability of Myc to induce apoptosis was markedly reduced in cells deleted for E2f1 but not E2f2 or E2f3. The authors proposed that the induction of specific E2F activities is an essential component in the MYC pathways that control cell proliferation and cell fate decisions.

The retinoblastoma tumor suppressor (Rb) pathway is believed to have a critical role in the control of cellular proliferation by regulating E2F activities. E2F1, E2F2, and E2F3 belong to a subclass of E2F factors thought to act as transcriptional activators important for progression through the G1/S transition. Wu et al. (2001) used a conditional gene targeting approach to demonstrate that combined loss of these 3 E2F factors severely affects E2F target expression and completely abolishes the ability of mouse embryonic fibroblasts to enter S phase, progress through mitosis, and proliferate. Loss of E2F function results in elevation of CIP1 (116899) protein, leading to a decrease in cyclin-dependent kinase activity and Rb phosphorylation. Wu et al. (2001) concluded that these findings suggested a function for this subclass of E2F transcriptional activators in a positive feedback loop, through downmodulation of CIP1, that leads to the inactivation of Rb-dependent repression and S phase entry. By targeting the entire subclass of E2F transcriptional activators, Wu et al. (2001) provided direct genetic evidence for their essential role in cell cycle progression, proliferation, and development. Wu et al. (2001) initially generated and interbred E2f1, E2f2, and E2f3 mutant mice, and found that although mice null for E2f1 and E2f2 were viable and developed to adulthood, mice null for E2f1 and E2f3 or E2f2 and E2f3 died early during embryonic development, at or just before embryonic day 9.5, pointing to a central role for E2F3 in mouse development.

Funke-Kaiser et al. (2003) identified 5 polymorphisms in the ECE1 gene (600423), a candidate for human blood pressure regulation, among a cohort of 704 European hypertensive patients. Electrophoretic mobility shift assays revealed the specific binding of E2F2 to ECE1b promoter sequences containing either allele of the C-338A polymorphism (600423.0002), with the -338A allele being associated with an increased affinity to E2F2 compared with -338C. The authors proposed a link between the cell cycle-associated E2F family and blood pressure regulation via a component of the endothelin system.

To address the function of E2F1, E2F2, and E2F3 in normal mammalian cells in vivo, Chen et al. (2009) focused on the mouse retina, which is a relatively simple central nervous system component that can be manipulated genetically without compromising viability and has provided considerable insight into development and cancer. The authors showed that unlike fibroblasts, E2f1-, E2f2-, and E2f3-null retinal progenitor cells or activated Muller glia can divide. Chen et al. (2009) attributed this effect to functional interchangeability with Mycn (164840). However, loss of activating E2fs caused downregulation of the p53 (191170) deacetylase Sirt1 (604479), p53 hyperacetylation, and elevated apoptosis, establishing a novel E2f-Sirt1-p53 survival axis in vivo. Chen et al. (2009) concluded that activating E2fs are not universally required for normal mammalian cell division, but have an unexpected prosurvival role in development.

Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles, Chong et al. (2009) examined the effects of E2f1, E2f2, and E2f3 triple deficiency in murine embryonic stem cells, embryos, and small intestines. They showed that in normal dividing progenitor cells, E2f1-3 function as transcriptional activators, but are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb (614041) as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f-responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. Chong et al. (2009) concluded that their work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.


Mapping

Lees et al. (1993) mapped the E2F2 gene to 1p36 by fluorescence in situ hybridization.


Animal Model

Iglesias et al. (2004) generated mice deficient in both E2f1 (189971) and E2f2. The mice developed nonautoimmune insulin-deficient diabetes and exocrine pancreatic dysfunction characterized by endocrine and exocrine cell dysplasia and a reduction in the number and size of acini and islets, which were replaced by ductal structures and adipose tissue. Mutant pancreatic cells exhibited increased rates of DNA replication but also of apoptosis, resulting in severe pancreatic atrophy. The expression of genes involved in DNA replication and cell cycle control was upregulated in the E2f1/E2f2 compound mutant pancreas. Iglesias et al. (2004) suggested that E2F1/E2F2 activity negatively controls growth of mature pancreatic cells and is necessary for the maintenance of differentiated pancreatic phenotypes in the adult.


REFERENCES

  1. Chen, D., Pacal, M., Wenzel, P., Knoepfler, P. S., Leone, G., Bremner, R. Division and apoptosis of E2f-deficient retinal progenitors. Nature 462: 925-929, 2009. [PubMed: 20016601] [Full Text: https://doi.org/10.1038/nature08544]

  2. Chong, J.-L., Wenzel, P. L., Saenz-Robles, M. T., Nair, V., Ferrey, A., Hagan, J. P., Gomez, Y. M., Sharma, N., Chen, H.-Z., Ouseph, M., Wang, S.-H., Trikha, P., and 10 others. E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature 462: 930-934, 2009. [PubMed: 20016602] [Full Text: https://doi.org/10.1038/nature08677]

  3. Funke-Kaiser, H., Reichenberger, F., Kopke, K., Herrmann, S.-M., Pfeifer, J., Orzechowski, H.-D., Zidek, W., Paul, M., Brand, E. Differential binding of transcription factor E2F-2 to the endothelin-converting enzyme-1b promoter affects blood pressure regulation. Hum. Molec. Genet. 12: 423-433, 2003. Note: Erratum: Hum. Molec. Genet. 12: 947 only, 2003. [PubMed: 12566389] [Full Text: https://doi.org/10.1093/hmg/ddg040]

  4. Iglesias, A., Murga, M., Laresgoiti, U., Skoudy, A., Bernales, I., Fullaondo, A., Moreno, B., Lloreta, J., Field, S. J., Real, F. X., Zubiaga, A. M. Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice. J. Clin. Invest. 113: 1398-1407, 2004. [PubMed: 15146237] [Full Text: https://doi.org/10.1172/JCI18879]

  5. Ivey-Hoyle, M., Conroy, R., Huber, H. E., Goodhart, P. J., Oliff, A., Heimbrook, D. C. Cloning and characterization of E2F-2, a novel protein with the biochemical properties of transcription factor E2F. Molec. Cell. Biol. 13: 7802-7812, 1993. [PubMed: 8246995] [Full Text: https://doi.org/10.1128/mcb.13.12.7802-7812.1993]

  6. Lees, J. A., Saito, M., Vidal, M., Valentine, M., Look, T., Harlow, E., Dyson, N., Helin, K. The retinoblastoma protein binds to a family of E2F transcription factors. Molec. Cell. Biol. 13: 7813-7825, 1993. [PubMed: 8246996] [Full Text: https://doi.org/10.1128/mcb.13.12.7813-7825.1993]

  7. Leone, G., Sears, R., Huang, E., Rempel, R., Nuckolls, F., Park, C.-H., Giangrande, P., Wu, L., Saavedra, H. I., Field, S. J., Thompson, M. A., Yang, H., Fujiwara, Y., Greenberg, M. E., Orkin, S., Smith, C., Nevins, J. R. Myc requires distinct E2F activities to induce S phase and apoptosis. Molec. Cell 8: 105-113, 2001. [PubMed: 11511364] [Full Text: https://doi.org/10.1016/s1097-2765(01)00275-1]

  8. Wu, L., Timmers, C., Maiti, B., Saavedra, H. I., Sang, L., Chong, G. T., Nuckolls, F., Giangrande, P., Wright, F. A., Field, S. J., Greenberg, M. E., Orkin, S., Nevins, J. R., Robinson, M. L., Leone, G. The E2F1-3 transcription factors are essential for cellular proliferation. Nature 414: 457-462, 2001. [PubMed: 11719808] [Full Text: https://doi.org/10.1038/35106593]


Contributors:
Ada Hamosh - updated : 1/6/2010
George E. Tiller - updated : 1/6/2005
Marla J. F. O'Neill - updated : 6/17/2004
Ada Hamosh - updated : 11/26/2001
Stylianos E. Antonarakis - updated : 8/3/2001
Alan F. Scott - updated : 9/20/1995

Creation Date:
Victor A. McKusick : 2/22/1995

Edit History:
terry : 04/01/2013
carol : 6/17/2011
alopez : 1/15/2010
terry : 1/6/2010
alopez : 9/26/2008
terry : 9/24/2008
alopez : 1/6/2005
carol : 6/17/2004
terry : 6/17/2004
alopez : 11/26/2001
alopez : 11/26/2001
terry : 11/26/2001
mgross : 8/3/2001
mark : 4/7/1996
carol : 2/22/1995