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Intrinsic and Extrinsic Factors That Influence Epigenetics
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Ivan Nalvarte, Joëlle Rüegg, Carlos Guerrero-Bosagna
A key factor responsible for the initiation of male sexual differentiation is the Y-chromosome encoded transcription factor SRY (sex-determining on the Y chromosome), which controls the expression of different genes involved in male gonadal development and thus the increase in perinatal testosterone levels (15,16). In the developing mouse testes, DNA demethylation of a regulatory region of the Sry gene occurs at 11.5 dpc and correlates with increased expression of Sry (17). This demethylation is testis specific and is believed to be mediated by GADD45 (growth arrest DNA damage-inducible 45) proteins that recruit DNA repair proteins to replace methylated cytosines by unmethylated ones (15). Interestingly, GADD45 proteins are also known to be involved in stress response (18), which could imply that environmental stress can affect early gonadal development and testosterone production. Increased gonadal sex hormones levels are needed for developmental reprogramming of the hypothalamus in a sexual dimorphic manner, for the development of reproductive organs, and for imprinting of sexual dimorphic behavior. In the prenatal brain of male rodents, it has been shown that aromatase (Cyp19a1) readily converts (aromatizes) testosterone into estrogen (E2) that is responsible for imprinting male-typical behavior (19,20). During this period, increase in the transcription-activating mark histone 3 (H3) acetylation is found at the Cyp19a1 gene in males, coinciding with their testosterone surge (21).
Tumor Suppressor Genes and Oncogenes
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
The p53 protein has three parts: a central DNA-binding domain in which mutations are usually of the missense type, a transcription domain (N-terminus) and a regulatory domain (C-terminus) in which mutations result in nonsense or stop codons. The protein murine double minute-2 (mdm-2) binds near the N-terminus of the protein. One of the genes activated by p53 is the p21 protein (WAF1), which inhibits the activity of cyclin-dependent kinases and which also binds to PCNA. Other genes include gadd45 and the protein bax (which promotes apoptosis).
The Molecular and Genetic Effects of Ultraviolet Radiation Exposure on Skin Cells
Published in Henry W. Lim, Herbert Hönigsmann, John L. M. Hawk, Photodermatology, 2007
Marjan Garmyn, Daniel B. Yarosh
Arrest in the G2 phase involves other p53-dependent factors, including 14-3-3 sigma (58) and GADD45 (growth arrest and DNA damage inducible gene) (59). GADD45 promotes G2/M arrest via nuclear export and kinase activity of Cdc2. Also p53-independent mechanisms (60) are involved in UVB-induced growth arrest.
GADD45B predicts lung squamous cell carcinoma survival and impacts immune infiltration, and T cell exhaustion
Published in Autoimmunity, 2023
Ying Lv, Zeyu Liu, Kai Xiong, Hailing Duan, Jiuyu Yang, Pan Liao
GADD45B gene belongs to the growth arrest and DNA damage-inducible 45 (GADD45) gene family, which also includes GADD45A and GADD45G. GADD45B is related to stress signals in physiological and environmental stress responses and is implicated in oncogenic stress that can lead to DNA repair, arrest of the cell cycle, cell apoptosis, survival, and ageing [11]. GADD45B can activate the p38/JNK pathway mediated by combining and activating the specific MTK1/MEKK4 kinase in response to environmental stress [12]. GADD45B can change the epigenetic program of α2-adrenergic receptors and can regulate the generation of local pro-inflammatory factors within the rodent amygdala; therefore, GADD45B regulates the social behaviours of adolescents epigenetically [13]. In stage-II colorectal cancer patients with reduced OS (overall survival) and PFS (progression-free survival) [14] and those suffering from papillary thyroid cancer receiving iodine radiotherapy and total thyroidectomy [15], the upregulation of GADD45B serves as a factor to independently predict patient prognosis. GADD45B is involved in the resistance to chemotherapy and aggressive growth of human embryonic carcinoma side population cells [16]. Silencing of GADD45B can reduce the migration and invasion of cholangiocarcinoma cells [17]. As demonstrated by these results, GADD45B promotes malignant phenotypes in multiple cancers. However, the related mechanism remains largely unclear.
The Effects of Quercetin on the Apoptosis of Human Breast Cancer Cell Lines MCF-7 and MDA-MB-231: A Systematic Review
Published in Nutrition and Cancer, 2022
Roghayeh Molani Gol, Sorayya Kheirouri
Loung et al. indicated that AF4-treated MDA-MB-231 cells accumulated in the G0/G1 phase, with a corresponding decrease in the number of cells in the S phase (84). In addition, Chou et al. in a study on MCF-7 cells showed that QT caused S phase arrest by alteration of the different cell cycle-regulation proteins (22). They found that QT reduced the levels of cyclins A and E, thymidylate synthase, CDK2, and p57 which are correlated with the S phase arrest (22). QT treatment also reduces p53 levels which plays an essential role in maintaining a balance between cell death and growth (135, 136). After DNA damage, p53 triggers cell cycle regulatory events and limits the proliferation of damaged cells (135). On the other hand, p53 modulates genes involved in cell cycle. GADD45, a p53-regulated and DNA damage-inducible protein, induces G2-M cell cycle arrest (137, 138). P21 protein is also regulated by p53 which inhibits CDK2 activity and leads to G1/S arrest (139). Neguyen et al. showed that QT treatment caused the activity of p53 signaling and p21 and GADD45 promoters and suggested that the enhanced activities might block the cell cycle (87). Thus, QT because of the inhibition of cell cycle progression leads to apoptotic cell death (22, 140).
Macrophages and brown adipocytes cross-communicate to modulate a thermogenic program following methamphetamine exposure
Published in International Journal of Hyperthermia, 2020
Manuel Sanchez-Alavez, Nikki Bortell, Liana Basova, Fahumiya Samad, Maria Cecilia Garibaldi Marcondes
The transcription of UCP1, PPARγ, and PGC1α, was upregulated in BA cultures by Meth, but not by NE, and this upregulation was prevented with NAC and with Catalase. In the GADD45 pathway, only GADD45γ was increased by Meth, and controlled by Meth + NE, as well as by NAC. On the other hand, when BA and macrophages were co-cultured, NE enhanced the transcription of UCP1 and GADD45α, and the effects of Meth were largely attenuated in comparison to BA alone. This suggests that macrophages can play a critical role at maintaining homeostasis in peripheral thermogenic sites. The GADD45 pathway is induced by environmental stress and is associated with DNA damage and other stress signals associated with growth arrest and apoptosis [51]. Distinct roles are attributed to each one of the subunits [52]. GADD45α is an RNA-binding protein, which can inhibit autophagy [53,54]. GADD45β and GADD45γ specifically interact with the Cdk1/CyclinB1 complex, with consequences to the cell cycle [55]. GADD45γ does not disrupt this complex, but can regulate cell cycle as well as other functions at the epigenetic level, by interacting with DNA double-strand break (DSB)-mediated changes in DNA methylation, and influencing early gene expression [56]. This mechanism described in association with neuronal development and learning [56], maybe active in other cell types. The GADD45γ/p38/ERRγ pathway was shown to regulate BAT thermogenesis [57]. While mice that lack PGC1α have only mild thermogenesis effects, mice that lack GADD45γ have important defects in UCP1 induction and in the thermogenic response in models of cold exposure [57]. GADD45γ is transcriptionally elevated by Meth in BA, regardless of macrophages in culture. In addition, NAC in BA single cultures prevents the transcription of this gene, making GADD45γ a good candidate for regulation of Meth hyperthermia. Experiments using knock out animals are necessary to identify the precise regulator, and whether the changes observed in BA can result in the modulation of hyperthermia in vivo.