HGNC Approved Gene Symbol: E2F5
Cytogenetic location: 8q21.2 Genomic coordinates (GRCh38): 8:85,177,154-85,214,518 (from NCBI)
Sardet et al. (1995) cloned E2F5 from a human fibroblast library using the 2-hybrid system with p130 (180203) as bait. Unlike E2F1 (189971), E2F4 (600659) and E2F5 do not bind with the RB1 (614041) gene product. In synchronized keratinocytes, E2F4 and E2F5 transcription is highest in mid-G1 phase before E2F-1 expression is detectable. E2F5 encodes a predicted 345-amino acid protein that is 69% identical to E2F4, with which it forms a distinct subclass of E2F-like molecules. Both E2F4 and E2F5 proteins have conserved DNA-binding domains and bind to p130 and p107 (116957).
Gross (2014) mapped the E2F5 gene to chromosome 8q21.2 based on an alignment of the E2F5 sequence (GenBank AY162833) with the genomic sequence (GRCh38).
SMAD3 (603109) is a direct mediator of transcriptional activation by the TGF-beta (190180) receptor (see 190181). Its target genes in epithelial cells include cyclin-dependent kinase (CDK; see 116953) inhibitors that generate a cytostatic response. Chen et al. (2002) defined how, in the same context, SMAD3 can mediate transcriptional repression of the growth-promoting gene MYC (190080). A complex containing SMAD3, the transcription factors E2F4, E2F5, and DP1 (189902), and the corepressor p107 preexists in the cytoplasm. In response to TGF-beta, this complex moves into the nucleus and associates with SMAD4 (600993), recognizing a composite SMAD-E2F site on MYC for repression. Previously known as the ultimate recipients of CDK regulatory signals, E2F4/E2F5 and p107 act here as transducers of TGF-beta receptor signals upstream of CDK. SMAD proteins therefore mediate transcriptional activation or repression depending on their associated partners.
Gaubatz et al. (2000) reported that simultaneous inactivation of E2f4 and E2f5 in mice resulted in neonatal lethality, suggesting that E2f4 and E2f5 perform overlapping functions during mouse development. Embryonic fibroblasts isolated from these mice proliferated normally and reentered from G0 with normal kinetics compared to wildtype cells; however, they failed to arrest in G1 in response to p16INK4A (CDKN2A; 600160). Thus, the authors concluded that E2F4 and E2F5 are dispensable for cell cycle progression but necessary for pocket protein-mediated G1 arrest of cycling cells.
Chen, C.-R., Kang, Y., Siegel, P. M., Massague, J. E2F4/5 and p107 as Smad cofactors linking the TGF-beta receptor to c-myc repression. Cell 110: 19-32, 2002. [PubMed: 12150994] [Full Text: https://doi.org/10.1016/s0092-8674(02)00801-2]
Gaubatz, S., Lindeman, G. J., Ishida, S., Jakoi, L., Nevins, J. R., Livingston, D. M., Rempel, R. E. E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Molec. Cell 6: 729-735, 2000. [PubMed: 11030352] [Full Text: https://doi.org/10.1016/s1097-2765(00)00071-x]
Gross, M. B. Personal Communication. Baltimore, Md. 7/28/2014.
Sardet, C., Vidal, M., Cobrinik, D., Geng, Y., Onufryk, C., Chen, A., Weinberg, R. A. E2F-4 and E2F-5, two members of the E2F family, are expressed in the early phases of the cell cycle. Proc. Nat. Acad. Sci. 92: 2403-2407, 1995. [PubMed: 7892279] [Full Text: https://doi.org/10.1073/pnas.92.6.2403]