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Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Alastair G. Stewart, Paul R. Tomlinson, Leslie Schachte
In addition to phosphorylating Rb, cyclin D–Cdk4 phosphorylates E2F-1, which also inhibits the interaction of E2F with Rb.194 Interestingly, a majority of hyperphosphorylated Rb exists in E2F complexes at the end of G1 and through S phase.195 Increased levels of Rb-free E2F complexes may be the result of release of E2F from other pocket-binding proteins (p107 or p130) or the de novo synthesis of E2F-1 protein.196,197 Thus, the phosphorylation of noncomplexed Rb and the synthesis of E2F would produce E2F complexes with transcriptional activity.184
Zearalenone: Insights into New Mechanisms in Human Health
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Cornelia Braicu, Alina Andreea Zimta, Ioana Berindan-Neagoe
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].
Precision medicine for colorectal cancer
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Candan Hızel, Şükrü Tüzmen, Arsalan Amirfallah, Gizem Çalıbaşı Koçal, Duygu Abbasoğlu, Haluk Onat, Yeşim Yıldırım, Yasemin Baskın
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).
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.
MicroRNA function in megakaryocytes
Published in Platelets, 2019
Sanjeev Raghuwanshi, Swati Dahariya, Syed Shahid Musvi, Usha Gutti, Ravinder Kandi, Ram Babu Undi, Itishri Sahu, Dushyant Kumar Gautam, Indira Paddibhatla, Ravi Kumar Gutti
Garzon et al. [7] compared the miRNAs expression profile of megakaryoblastic leukemic cell lines with that of CD34+ progenitors derived MKs, data demarcate the up-regulation of miR-99a, miR-101, miR-126, miR-135, and miR-20 in megakaryoblastic leukemic cell lines. Other studies also showed the oncogenic potential of miR-99a [38]. Further, Kandi et al. [19] did a comparative study between neonatal (CB)- and adult (PB)- CD34+ progenitor derived MKs and observed up-regulation of miR-99a in neonatal MKs, whereas miR-99a target, CTDSPL, a phosphatase-like tumor suppressor, was down regulated in neonatal MKs, which in turn led to the phosphorylation of RB and accumulation of E2F1. The E2F1 promotes cell cycle progression by increasing cyclins (CyclinD1, cyclin D2 and Cyclin D3) expression. All together data suggests that the high levels of miR-99a maintain the high cell proliferation potential of neonatal MKP (Figure 4).
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
E2F1 belongs to the transcription factor family named E2Fs, characterized by activating (E2F1––E2F3a), repressing (E2F3b––E2F5) or inhibiting (E2F6––E2F8) activities on the transcription of many genes including cell cycle genes [4]. E2F1 (Figure 1(a)) contains a DNA binding domain (DBD) a transactivation domain (TD) and a dimerization domain (DD). DBD allows the binding to gene promoter thus inducing transcription. DD is necessary to bind the dimerization partner (DP) which allows DNA binding. Finally, via TD, E2F1 interacts with its inhibitor retinoblastoma protein (pRB) which binds to E2F1-DP in resting cells. In the presence of proliferation stimuli, pRb is phosphorylated by cyclin D/cdk4-6 (cyclin dependent kinase) kinase and thus released from the complex E2F1/DP (Figure 1(b)). Once detached from pRb, E2F1/DP triggers the transcription of different genes including cyclin E1 that in turn, bound to its cdk2, phosphorylates pRb further allowing E2F1-DP release and activation. Not only E2F1/DP promotes cell growth, it can also activate apoptosis via p53-dependent and p53-independent mechanisms, thus highlighting its double biological role.