E2F3

Official Full Name

E2F transcription factor 3

Organism

Homo sapiens

GeneID

1871

Background

This gene encodes a member of a small family of transcription factors that function through binding of DP interaction partner proteins. The encoded protein recognizes a specific sequence motif in DNA and interacts directly with the retinoblastoma protein (pRB) to regulate the expression of genes involved in the cell cycle. Altered copy number and activity of this gene have been observed in a number of human cancers. There are pseudogenes for this gene on chromosomes 2 and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

Synonyms

E2F-3;

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Detailed Information

E2F transcriptional regulators often lead to abnormal activities such as cell carcinogenesis and abnormal expression of E2F in tumor tissues and tumor cells. As an important member of the E2F family, E2F3 is involved in cell proliferation and regulation and is closely related to genes such as p53 and Rb. Julian et al. found that E2F3 is different from other family members and is divided into two subunits, E2F3a and E2F3b, which are encoded by the same gene locus. The E2F3 protein consists of 465 amino acids with a molecular weight of 49 KD.

E2F3 can form a dimer through cyclin D1, participate in the regulation of the cell cycle, and is associated with a variety of oncogenic and tumor suppressor genes. The expression of E2F3 in various tumors has increased, which has become a hot spot in cancer research. Retinoblastoma protein (pRB) is a well-established tumor suppressor whose tumor inhibition depends to a large extent on the regulation of E2F transcription factors. Tang et al. found that E2F regulates the cell cycle and relies on the transcriptional regulation of key components of the cell cycle. Recent studies have found that high expression of E2F3 is associated with the occurrence and development of a variety of human tumors, including bladder cancer and prostate cancer.

E2F3 Regulates Cell Proliferation

The occurrence and development of tumors depend on the functional status of the p16Ink4a-Rb-E2F3 signaling pathway and the Arf-mdm2-p53 signaling pathway. E2F3 can function through these two networks and regulate cell proliferation. Studies have found that in normal cells, E2F3 is directly involved in the regulation of Arf transcription. In wild-type mouse embryonic fibroblasts, E2F3 binds to the promoter of Arf, inhibiting its transcription, and other members of the E2F family are not involved in this regulation. After knocking out E2F3, the transcriptional activity of Arf was significantly inhibited, and the proliferation of mouse embryonic fibroblasts was significantly enhanced. Experiments have shown that the expression level of E2F3 is the key to the role of Arf in monitoring abnormal cell proliferation.

To study the role of E2F3 in vivo, the researchers constructed E2F3-deficient mice, which had embryo survival rates that were only one-fourth expected, suggesting that E2F3 is important in normal development. The study also initially analyzed E2F3-deficient mouse embryonic fibroblasts to determine the molecular mechanisms underlying them. The results were found to be related to multiple genes, including B-my b, cyclin A, cdc 2, cdc 6 and DHER. The expression of these genes is related to E2F3, which in turn affects cell proliferation. It has also been confirmed that E2F3-deficient cells are defective in cell cycle and proliferation. However, when the cells restored the expression of E2F3, their cell proliferation ability returned to normal. Rady et al. found in human β cells that overexpressed E2F3 could increase the proliferation of β cells, but had no significant effect on apoptosis.

Amplification and Expression of E2F3 in Tumor

Shen et al. found that there is gene amplification in the chromosome 6p22 locus in a variety of tumors. Bladder cancer was analyzed by multiplex quantitative polymerase chain reaction, and the results showed that there was gene amplification at chromosome 6p22. One study found gene amplification at chromosome 6p22 in cell lines TCCSUP and HT1376 of bladder cancer. Further studies revealed that the expanded region was a 65Mb region containing 12 genes, which spanned the E2F3 gene locus. After excluding other genes, the amplified gene was identified as E2F3. The study also analyzed the expression of E2F3 and the clinical stage and pathological grade of the tumor, showing that the higher the clinical stage and pathological grade of the tumor, the higher the positive expression rate of E2F3. About 2/3 of prostate cancers have high expression of E2F3, and Bilke et al. found through multivariate analysis that E2F3 can be used as an independent factor to predict the overall survival of patients with prostate cancer.

Relationship Between E2F3 and Tumorigenesis and Development

Recent studies have found that miRNAs such as miR-449a and miR-125b miR-432 inhibit cell proliferation or induce apoptosis by inhibiting E2F3. Ma et al. found that in proliferating cells, miR-432 inhibits E2F3 mRNA, resulting in a decrease in transcription factor E2F3 in the nucleus to inhibit transcription of cell cycle genes and ultimately lead to the arrest of G1-phage.

E2F3 Figure 1. Suppression of E2F3 mRNA by miR-432 resulted in E2F3 decreasing (Ma, et al. 2017)

Ren et al. studied the relationship between miR-449a and E2F3 in lung cancer and found that cell cycle arrest was arrested in G1 phase and cell proliferation was inhibited after overexpression of miR-449a in lung cancer A549 and 95D cell lines. E2F3 is a direct target of miR-449a. When it is inhibited by miR-449a, the expression of E2F3 is decreased, which leads to inhibition of cell proliferation. After silenced the endogenous E2F3, the same result was obtained. Some researchers have also studied in bladder cancer and prostate cancer cells, and the results show that the cell proliferation ability is significantly improved after overexpression of E2F3 in bladder cancer cells.

The study found that in prostate cancer cells, pRB-deficient DU145 showed a decrease in proliferative power after overexpression of E2F3, but had no significant effect on proliferation in pRB-positive cell line PC3, suggesting that E2F3 may be involved in the pRB regulatory signaling pathway. Studies have shown that E2F3 regulates multiple tumor-associated genes in prostate cancer. E2F3 related studies in melanoma also found that E2F3 expression was significantly increased in melanoma cells Mewo, E2F3 expression was decreased after overexpression of miR-203, cell proliferation ability decreased and aging occurred. The expression of E2F3 in laryngeal squamous cell carcinoma was significantly higher than that in adjacent normal laryngeal mucosa (P<0.001), and the lower the degree of differentiation, the higher the expression level (P<0.05), and the 5-year survival rate was lower than that of negative expression. (P<0.05).

References:

Julian, L. M., Vandenbosch, R., Pakenham, C. A., Andrusiak, M. G., Nguyen, A. P., & Mcclellan, K. A., et al. (2013). Opposing regulation of sox2 by cell-cycle effectors e2f3a and e2f3b in neural stem cells. Cell Stem Cell, 12(4), 440-452.
Tang, W., Tang, J., Qin, J., Geng, Q., Zhou, Z., & Li, B., et al. (2013). Involvement of down-regulated e2f3 in hirschsprung's disease. Journal of Pediatric Surgery, 48(4), 813-817.
Rady, B., Chen, Y., Vaca, P., Wang, Q., Wang, Y., & Salmon, P., et al. (2013). Overexpression of e2f3 promotes proliferation of functional human β cells without induction of apoptosis. Cell Cycle, 12(16), 2691-2702.
Shen, H., Morrison, C. D., Zhang, J., Willie Underwood, I., Yang, N., & Frangou, C., et al. (2013). 6p22.3 amplification as a biomarker and potential therapeutic target of advanced stage bladder cancer. Oncotarget, 4(11), 2124-2134.
Bilke, S., Schwentner, R., Yang, F., Kauer, M., Jug, G., & Walker, R. L., et al. (2013). Oncogenic ets fusions deregulate e2f3 target genes in ewing sarcoma and prostate cancer. Genome Research, 23(11), 1797-1809.
Ma, M., Wang, X., Chen, X., Cai, R., Chen, F., & Dong, W., et al. (2017). Microrna-432 targeting e2f3 and p55pik inhibits myogenesis through pi3k/akt/mtor signaling pathway. Rna Biology, 14(3), 347-360.
Ren, X. S., Yin, M. H., Zhang, X., Wang, Z., Feng, S. P., & Wang, G. X., et al. (2014). Tumor-suppressive microrna-449a induces growth arrest and senescence by targeting e2f3 in human lung cancer cells. Cancer Letters, 344(2), 195-203.

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