Zearalenone: Insights into New Mechanisms in Human Health
Dongyou Liu in Handbook of Foodborne Diseases, 2018
Medium doses of ZEA, 2 mg/kg, alter the spermatogenesis process by causing greater expression of E2F1 and cyclin D genes, but at 4 mg/kg downregulates the expression of these genes. E2F1, when overexpressed, causes DNA damage and leads to apoptosis. The overtranscription of cyclin D1 is also an apoptosis promoter. At the histological level, this is seen as elevated apoptosis along with DNA fragmentation throughout all cell layers, especially in the case of spermatogonia. Surprisingly, even when E2F1 is underexpressed by a high concentration of ZEA, the cells still go through apoptosis [64]. In CD1 mice, the spermatozoa abnormality is increased, and the total spermatozoa count is decreased. The Sertoli cells proliferated, along with taking the place of spermatogonia and spermatocytes. In the spermatogonia cell, the VEGFa, Sycp3, Ccna1, and Grth genes were underexpressed, whereas the Sycp1 gene was overexpressed. The expression of androgen receptor is also decreased, along with the tumor suppressor genes p53 and p21 [65]. The Sertoli cells are damaged at multiple sites. The nucleus, F-actin, and α-tubulin acquire irregular shapes; the mitochondria and Golgi apparatus are disrupted [66].
Introducing Molecular Biology of Head and Neck Cancer
John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford in Head & Neck Surgery Plastic Surgery, 2018
E6 functions by binding to the p53 protein and it also binds to a cellular protein E6AP (encoded by the UBE3A gene [ubiquitin-protein ligase E3A]), which promotes the poly-ubiquitylation of p53 and thus targets p53 protein to the 26S proteasome for degradation.141, 142 E7 functions by binding to the RB protein and preventing it from interacting with E2Fs, thus allowing E2F-regulated genes to become transcribed.143 Recent studies have also identified that binding of E7 to RB also promotes degradation of the RB protein by the ubiquitin—proteasome route.144, 145 In HPV+ cancers, E6 and E7 expression appear to be ubiquitous, further supporting a role for retaining expression of these to maintain continued cell cycling. In HPV+ cancers, E2F1 expression was also often increased (in approximately 19% of tumours); this would be expected to result from inactivation of the RB and TP53 genes by E7 and E6 respectively.
Precision medicine for colorectal cancer
Debmalya Barh in Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Thymidylate synthase (TYMS) is crucial enzyme for providing essential nucleotide precursors (de novo pyrimidine synthesis) in order to maintain DNA synthesis and repair. Respectively, TYMS is implicated in the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) (Carreras and Santi, 1995). Hence, TYMS expression is a rate-limiting step for cell proliferation as well as for cancer growth (Rustum, 2004). Compelling evidence from several clinical studies have demonstrated that TYMS protein and mRNA levels were higher in different cancers (Berger and Berger, 2006), including breast cancer, lung cancer, gastric cancer, and CRC (Yamada et al., 2001; Kamoshida et al., 2004; Popat et al., 2006), and this increase in TYMS levels has been associated with poor clinical outcome in these cancers. It is also shown that TYMS expression correlates closely with transcription factor E2F1 expression in colon cancer specimens. In accordance with this TYMS—E2F1 correlation TYMS could be considered as an E2F1-regulated enzyme, which is essential for DNA synthesis and repair (Kasahara et al., 2000; Rahman et al., 2004). Additionally, an in vitro study in immortalized NIH/3T3 mouse fibroblast cells underlined oncogene-like activity of TYMS that suggests a connection between TYMS-regulated DNA synthesis and the induction of a neoplastic phenotype (Rahman et al., 2004; Bertino and Banerjee, 2004).
E2F1 as a molecular drug target in ovarian cancer
Published in Expert Opinion on Therapeutic Targets, 2019
Rossella Farra, Barbara Dapas, Mario Grassi, Fabio Benedetti, Gabriele Grassi
It is more than a decade that E2F1 overexpression has been documented in different OC cell lines and tissues. Increased expression of E2F1 has been associated with advanced histopathologic grade of OC [5] and mitotic index [6]. Notably, E2F1 overexpression has been also associated to unfavorable disease-free and overall survival, stressing its significant contribution to OC [6,7]. More recently, the significance of E2F1 in OC has been further refined by showing that its expression is significantly increased in the more aggressive HGSC compared to the less aggressive LGSC [8] forms of OC. Despite the documented OC promoting effects, E2F1 can also down regulate OC progression favoring apoptosis. It has been shown that increased activation of E2F1 was positively associated with more favorable patient survival [9]. The apparent contrasting roles of E2F1 is however not a peculiarity of OC since this phenomenon has been described also in hepatocellular carcinoma (HCC) [10]. In HCC, the contrasting effect of E2F1 has been related to the developmental stage of the tumor. While in the first stage, E2F1 promotes both cell proliferation and apoptosis with this last being an attempt to reducing tumor progression, in the more advanced stages, the pro-apoptotic functions are progressively lost while the proliferative effect predominates. In OC, no precise explanations for the contrasting effects of E2F1 have been proposed so far. Despite this, it would not be surprising a situation comparable to that observed in HCC.
Delayed neutrophil apoptosis in granulomatosis with polyangiitis: dysregulation of neutrophil gene signature and circulating apoptosis-related proteins
Published in Scandinavian Journal of Rheumatology, 2020
M Surmiak, M Hubalewska-Mazgaj, K Wawrzycka-Adamczyk, J Musiał, M Sanak
Our mRNA quantification also included another transcription factor participating in apoptosis, namely E2F1. E2F1 can affect apoptosis directly by a p53-independent mechanism or in concert with p53. The p53-dependent pathway of E2F1 regulates the expression of apoptosis-related genes by modulating p53 expression. This is achieved by a negative effect on the p53 inhibitor (MDM2) or by enhanced transcription of p53 cofactors (ASPP1, ASPP2, or JMY). Independent E2F1 activity induces pro-apoptotic genes, including CASP3, CASP7, PMAIP1, and DIABLO, by directly binding to their promoters (40, 41). Decreased expression of E2F1 target genes and their correlation with E2F1 mRNA suggest the importance of this transcription factor in mechanisms regulating the neutrophil apoptosis pathway in GPA.
Up-regulation of miR-144 and miR-375 in the human gastric cancer cell line following the exposure to extremely low-frequency electromagnetic fields
Published in International Journal of Radiation Biology, 2021
Fatemeh Aalami Zavareh, Soheila Abdi, Maliheh Entezari
Overexpression of miR-34a in lung cancer cells (LLC) of mouse model following the exposure to LF-MF (0.4 T, 7.5 Hz, produced by rotating NdFeB permanent magnets) for 35 days was reported by Ren et al. in 2017. They found that LF-MF inhibited tumor growth and induced cell growth arrest and cell senescence in lung cancer cells. LF-MF enhanced the miR-34a transcription and decreased the E2F1/E2F3 expression, which affects cell proliferation and cell senescence (Ren et al. 2017). The use of miRs in gene therapy can be an effective way to prevent the progression of cancers, such as gastric adenocarcinoma (Esquela-Kerscher and Slack 2006). Gastric Cancer (GC) is a heterogeneous disease with various reasons and a high mortality rate worldwide (Ferro et al. 2014). It was shown that miRs play an important role in the progression of gastric cancer (Ferro et al. 2014). It was shown that miR-144 and miR-375 are downregulated in multiple cancers and tumor cell lines and play a significant role in cell proliferation and metastasis (Wang et al. 2011; Iwaya et al. 2012). The reduced expression level of miR-144 has been seen in colorectal cancer (CRC), gastric cancer (GC), and squamous cervical cancer. Reduction of miR-375 expression has been observed in cervical cancer (Wang et al. 2011). Downregulation of miR-144 and miR-375 in tumor cells, suggesting them as a new therapeutic target in cancer.
Related Knowledge Centers
- P53
- Protein
- Retinoblastoma Protein
- Tumor Suppressor Gene
- Apoptosis
- Gene
- Transcription Factor
- Cell Cycle
- DNA-Binding Domain
- Protein–Protein Interaction