E2F1

Official Full Name

E2F transcription factor 1

Organism

Homo sapiens

GeneID

1869

Background

The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein and another 2 members, E2F2 and E2F3, have an additional cyclin binding domain. This protein binds preferentially to retinoblastoma protein pRB in a cell-cycle dependent manner. It can mediate both cell proliferation and p53-dependent/independent apoptosis. [provided by RefSeq, Jul 2008]

Synonyms

RBP3; E2F-1; RBAP1; RBBP3;

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Detailed Information

The cell cycle-associated transcription factor E2F1 is a member of the E2F family of cell cycle-associated transcription factors. Activation of E2F1 transmits signals to the nucleus, pushing the cell cycle from the G1 phase to the S phase, and is an important transcription factor in the cell cycle progression. In recent years, studies have found that E2F1 is involved in tumor cell metabolism reprogramming in addition to regulating cell cycle, and plays an important role in the occurrence and development of tumors.

Effect of E2F1 on Traditional Cell Cycle

Cell proliferation requires four stages, of which G1 / S is a key point regulating cell proliferation. The E2F family includes eight family members, E2F1 to E2F8, which encode transcriptional regulators. E2F is an important regulator of cellular processes and plays an important role in the G1 / S phase transition of the mammalian cell cycle. Among them, E2F1 is the most widely studied as a positive positive regulator in the family. In the early G1, E2F1 was inhibited by its specific binding to Rb to form a complex. In the middle and late G1, cyclin binds to the corresponding cyclin dependent kinase (CDKs) to activate CDKs and phosphorylate Rb. E2F1 is released from the Rb protein and activated, causing the cells to enter the S phase from the G1 phase. E2F1 is involved in a variety of physiological and pathological processes. In addition to promoting cell proliferation from G1 to S phase, E2F1 can induce apoptosis through p53 and non-p53 pathways, and has both cancer-promoting and tumor-suppressing activities. It has become a highly controversial gene in the field of tumor gene research.

E2F1 Figure 1. Cell cycle regulation of E2F1 by ubiquitination. (Dubrez 2017)

Clinical studies have shown that E2F1 is abnormally expressed in many tumors such as breast cancer, prostate cancer, and pancreatic cancer, and is closely related to tumor progression, metastasis, and prognosis. However, in primary hepatocellular carcinoma (HCC), although a large number of experiments have demonstrated that E2F1 expression in cancer tissues or cells is significantly enhanced relative to normal tissues and cells. However, the enhancement of its expression is to promote the proliferation of tumor cells or increase the apoptosis of cells. Lv et al. found that overexpression of E2F1 up-regulated the expression of H19, thereby promoting the expression and invasion of HepG2 cells. Chen et al. found that a decrease in HepG2 cells was observed after inhibition of E2F1 expression by siRNA. Studies have shown that high expression of E2F1 in human hepatocarcinoma tissues is also associated with poor prognosis of liver cancer, and overexpression of E2F1 can activate AKT signaling pathway to promote tumor cell survival, suggesting that high expression of E2F1 may promote the occurrence and development of liver cancer.

E2F1 and Glucose Metabolism

In addition to affecting cell cycle progression and cell proliferation through transcriptional regulation, E2F1 is also found to be closely related to metabolism. E2F1 knockout mice observed significant metabolic disorders relative to mice lacking other E2Fs family components, manifested as impaired glucose homeostasis, mitochondrial dysfunction, and decreased pancreatic volume. E2F1 in pancreatic beta cells directly regulates Kir6.2, an important component of the ATP pathway involved in glucose-induced regulation of insulin secretion. Deletion of E2F1 leads to decreased expression of Kir6.2, abnormal insulin secretion and abnormal glucose tolerance. E2F1 also activates the expression of pyruvate dehydrogenase kinase 4 (PDK4). PDK4 inhibits the decarboxylation of pyruvate into acyl-CoA by phosphorylation of pyruvate dehydrogenase complex (PDC), thereby inhibiting the tricarboxylic acid cycle and oxidative phosphorylation to form ATP. Therefore, activation of E2F1 can inhibit the oxidative metabolism of glucose by increasing the expression of PDK4. Moreover, E2F1 activates 6-phosphofructokinase-2 (PFK2), a bifunctional enzyme. It catalyzes the fructose of 6-phosphate to fructose 2,6-diphosphate, which allosterically activates the glycolytic rate-limiting enzyme 6-phosphate fructokinase-1, affecting the overall rate of glycolysis and plays a key role in tumor development.

E2F1 Targeted Therapy

At present, there are few treatments for cell cycle therapy, especially for E2F1 targets. When Valle et al. used non-steroidal anti-inflammatory drugs (diclofenac, indomethacin) to treat ovarian cancer cells, cell cycle inhibition was observed in tumor cells. Further studies have found that E2F1 is down-regulated in RNA and protein levels, and over-expressed E2F1 can restore the growth inhibition of cancer cells caused by the above drugs. It is speculated that diclofenac and indomethacin may inhibit cancer cells by down-regulating the expression of E2F1.

Gemcitabine, a first-line drug for tumor chemotherapy, mainly acts on the DNA synthesis phase of tumor cells, ie, the S phase of the cell cycle, and under certain conditions, can prevent the progression from G1 to S phase. Lai et al. found that the use of a glucose carrier inhibitor, CG-5, inhibits the expression of ribonucleotide reductase M2 (RMM2) in gemcitabine-resistant human pancreatic cancer cells (Panc-1GemR cells) by inhibiting E2F1. RMM2 is a key gene for the chemotherapy drug platinum and gemcitabine resistance. In addition to reducing the sensitivity of tumors to chemotherapeutic drugs, its overexpression is often closely related to tumor invasion and metastasis. Inhibition of E2F1 leads to a decrease in RMM2 expression, which increases the sensitivity of pancreatic cancer cells to gemcitabine and enhances drug treatment.

References:

Lv, J., Yu, Y. Q., Li, S. Q., Luo, L., & Wang, Q. (2014). Aflatoxin b1 promotes cell growth and invasion in hepatocellular carcinoma hepg2 cells through h19 and e2f1. Asian Pac J Cancer Prev, 15(6), 2565-2570.
Chen, Y. L., Uen, Y. H., Li, C. F., Horng, K. C., Chen, L. R., & Wu, W. R., et al. (2013). The e2f transcription factor 1 transactives stathmin 1 in hepatocellular carcinoma. Annals of Surgical Oncology, 20(12), 4041-4054.
Dubrez, L. (2017). Regulation of e2f1 transcription factor by ubiquitin conjugation. International Journal of Molecular Sciences, 18(10), 2188.
Valle, B. L., Theresa, D., Becker, K. G., Wood, W. H., Yongqing, Z., & Wersto, R. P., et al. (2013). Non-steroidal anti-inflammatory drugs decrease e2f1 expression and inhibit cell growth in ovarian cancer cells. Plos One, 8(4), e61836.
Lai, I. L., Chou, C. C., Lai, P. T., Fang, C. S., Shirley, L. A., & Yan, R., et al. (2014). Targeting the warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells. Carcinogenesis, 35(10), 2203.

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