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Proteins and proteomics
Published in Firdos Alam Khan, Biotechnology Fundamentals, 2018
The ubiquitin pathway has been involved in the pathogenesis of several diseases and genetic disorders such as neurodegenerative disorders where different isoforms of Ubiquilin-1 are found in lesions associated with Alzheimer’s and Parkinson’s disease. Higher levels of Ubiquilin in the brain have been shown to decrease malformation of amyloid precursor protein (APP), which plays a key role in triggering Alzheimer’s disease. Conversely, lower levels of Ubiquilin-1 in the brain have been associated with increased malformation of APP. A frameshift mutation in Ubiquitin B can result in a truncated peptide missing the C-terminal glycine. This abnormal peptide, known as UBB + 1, has been shown to accumulate selectively in Alzheimer’s disease and other tauopathies. In addition, Angelman syndrome is caused by a disruption of UBE3A, which encodes a Ubiquitin ligase (E3) enzyme termed E6-AP, and von Hippel—Lindau syndrome involves disruption of a Ubiquitin E3 ligase termed the VHL tumor suppressor, or VHL gene. Also 3-M syndrome is an autosomal-recessive growth retardation disorder associated with mutations of the Cullin7 E3 Ubiquitin ligase.
Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
Cullin RING E3 ubiquitin ligases (CRLs) are multi-subunit complexes that catalyze the transfer of ubiquitin to specific substrate proteins. The complex of cullin1 (CUL1), S-phase kinase associated protein 1 (SKP1), and mammalian F-box protein β-transducin repeat-containing protein (β-TRCP) is a CRL known as CRL1β-TRCP. The β-TRCP of CRL1β-TRCP binds to IκBα and promotes its ubiquitination and degradation (Yaron et al., 1998). A 10 amino acid phosphopeptide segment of IκBα is both necessary and sufficient to mediate its binding to CRL1β-TRCP and subsequent ubiquitination and degradation (Yaron et al., 1997; Yaron et al., 1998). Dr. Deshaies’ and Crews’ groups designed and synthesized a series of hybrid molecules named PROTACs consisting of the IκBα phosphopeptide and a ligand of target proteins such as methionine aminopeptidase 2 (Sakamoto et al., 2001), ERα, and AR (Sakamoto et al., 2003). Although the β-TRCP-recruiting PROTACs induce ubiquitination and degradation of target proteins in vitro, they have low activity in cells, presumably because of the poor cell permeability of the employed peptide. To overcome this problem, the IκBα phosphopeptide was replaced by a hydroxyproline-containing pentapeptide from hypoxia-inducible factor a (HIF-1a), which is recognized by von Hippel-Lindau (VHL). VHL is a substrate recognition component of an E3 ubiquitin ligase complex containing cullin 2 (CUL2), RING-box protein 1 (RBX1), elongin B (ELOB), and elongin C (ELOC). The CUL2-RBX1-ELOB-ELOC-VHL complex (known as CRL2VHL) directs the ubiquitylation and subsequent proteasomal degradation of HIF-1a under normoxic conditions. VHL-recruiting PROTACs, consisting of the HIF-1a pentapeptide and a ligand of ERα or AR, are cell permeable and induce significant degradation of ERα and AR at 12.5 and 50 μM, respectively (Rodriguez-Gonzalez et al., 2008).
Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Metabolic alterations in cancer cells are mainly driven by oncogenic pathways. Aberrant activation of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), MYC or hypoxia-inducible factor (HIF) a have been shown to be closely associated with altered metabolism in cancers. PI3K activates AKT1, which stimulates aerobic glycolysis by promoting glucose uptake and activation of glycolytic enzymes such as hexokinase and PFK-2/ FBPase-2 (Elstrom et al., 2004). mTOR is a master regulator of energy homeostasis that integrates information from growth factors, energy and nutrient availability, and oxygen levels to direct cell proliferation. (Guertin and Sabatini, 2007). An activated mTOR in cancer thus promotes unchecked biogenesis by stimulating ribosome synthesis, mRNA translation, lipogenesis and mitochondrial metabolism (Guertin and Sabatini, 2007). MYC is an oncogenic transcription factor that drives anabolism by literally up-regulating all genes involved in glycolysis and glutaminolysis (Dang, 2013). Moreover, MYC also induces RNA polymerase I and II, thereby promoting gene transcription and translation (Rahl et al., 2010). Accordingly, MYC-driven cancers exhibit strong dependence on glucose and glutamine (Wise et al., 2008). HIFa are transcription factors normally activated by hypoxia to activate transcription of multiple genes involved in glucose uptake, glycolysis and lactate production (Kim et al., 2006). In cancer cells, HIFa activity can be induced by oncogenic signaling such as PI3K/AKT or inactivating mutations of HIFa E3 ubiquitin ligase (VHL) (Kamura et al., 2000). Contrary to the above tumorigenic factors, AMPK functions as a metabolic suppressor that opposes the action of AKT1/mTOR in response to low energetic levels (a high AMP/ATP ratio), leading to repressed anabolism and cell proliferation (Gwinn et al., 2008). Cancer cells actively suppress the AMPK signaling pathway to engage anabolic pathways despite metabolic stress in the tumor microenvironment. For instance, LKB1, the upstream activator of AMPK, is frequently inactivated in cancers (Hearle et al., 2006; Matsumoto et al., 2007). Taken together, dysregulated cellular metabolism is an essential component of oncogenic transformation.
Comparison of carcinogenic potency across life stages: implications for the assessment of transplacental cancer risk
Published in Journal of Toxicology and Environmental Health, Part A, 2019
R. Dzubow, C. Fields, G. Ginsberg, M. Sandy, M. Mabson, B. Foos
Another uncertainty is whether cancer is observed in unique target organs after TP-only exposure. The best evidence for this in the current dataset is the kidney, an example which involves two genotoxicants, one at a Tier 1 level of evidence (Figure 4). However, as previously described this is still limited evidence and the kidney tumor response from TP exposure was 10% or less. The early life origins of kidney cancer in animals or humans has not been a research topic although evidence of a genetic component involving inheritance of a deficient Von Hippel-Lindau (VHL tumor suppressor) gene is consistent with an early life susceptibility (Ashouri et al. 2015). Prenatal genotoxicant exposure that produces a deficiency in the renal VHL gene may be a key predisposing factor for later emergence of renal cancer, with this genetic damage being more likely during a period of rapid growth and development than in the stable adult kidney. The lack of a PN kidney response in these two cases may be due to the rapid development of liver metabolizing enzymes which may prevent substantial amounts of chemical from reaching the kidney in the PN period.
Epigenotoxicity: a danger to the future life
Published in Journal of Environmental Science and Health, Part A, 2023
Farzaneh Kefayati, Atoosa Karimi Babaahmadi, Taraneh Mousavi, Mahshid Hodjat, Mohammad Abdollahi
Epigenetic changes in RCC are persistent, and critical signaling routes are genetically downregulated by abnormal methylation in the gene’s promoter involved in signaling pathways or by unusual expression of microRNAs. Epigenetic changes may be biomarkers for RCC diagnosing and prognosis and predicting therapeutic reply in RCC patients.[217] 31-CpG-based epigenetic signatures are linked to Clear cell renal cell carcinoma (ccRCC).[218] The most interesting epigenetic mechanism in ccRCC is common mutations in chromatin regulator genes that accompany Von Hippel Lindau’s (VHL) deactivation, hypoxia-inducible factors (HIF), and the TSG pathway. This allows tumor cell survival in a characteristic situation of pseudo-hypoxia. By loss of heterozygosity, mutation, or promoter hypermethylation, the VHL gene is inactivated in sporadic ccRCC. Several miRNAs have been connected to the VHL-HIF pathway. Particularly, MIR-30c downregulation in RCC is associated with loss of VHL. lncRNA expression profile in VHL-wild type and VHL-mutant RCC cell lines were studied and indicated that LncRNA-SARCC was differentially regulated in a VHL dependent manner in RCC cell lines and tumor samples.[219] Treating human embryonic kidney cells (HEK-293) with 0.5 and 1 μM concentrations of arsenic, resulted in the upregulation of the IL-8 gene due to the increased histone acetylation. In this study, the relationship between arsenic exposure and RCC was demonstrated by assessing KIM-1 as a reliable biomarker for renal carcinoma.[220]
Molecular toxicology and carcinogenesis of fumonisins: a review
Published in Journal of Environmental Science and Health, Part C, 2020
Ruth Nabwire Wangia-Dixon, Kizito Nishimwe
In terms of DNA methylation, epigenetic changes in mammalian DNA is mainly characterized by DNA methylation occurring in cytosine and adenosine.107,109 For instance, in CpG islands of gene promoter, DNA methylation suppresses gene transcription, which results in gene silencing.107,109,110 CpG islands are DNA regions with much higher GC frequency of more than 50% compared to the other regions.107 In HK-2 cells, fumonisin B1 is shown to induce changes on the global DNA methylation.109,110 While Clone 9 rat kidney cells and the NRK-52E liver epithelial cells did not show significant dose related effects on DNA methylation when exposed to fumonisin B1 (1-50 µM) over 24-hours, CpG promoter specific genes such as VHL gene in both cells; c-Myc in Clone 9 and p16 gene in NRK-52E, were methylated.109,110 For HepG2 cells, fumonisin B1 at 200 µM was shown to increase hypomethylation in DNA by downregulating the activities of DNA methyltransferases and upregulating MBD2.109–111 DNA methylation significantly contributes to chromatin instability and tumorigenesis. Oxidative stress associated with fumonisin B1 toxicity is speculated to also contribute to indirect genotoxic action on mammalian cells, mediated by the cytotoxic effects on DNA, protein synthesis and mitochondrial injury.71,112 Nonetheless, studies in animal models show no visible adducts formation detectable after exposure to fumonisin B1, which further corroborates lack of direct genotoxicity associated with fumonisin B1 exposures.92 In the past two decades, researchers have confirmed the carcinogenicity and tumor promotion activities of fumonisin B1 in rodent models.92–94 In male Fischer 344 rats, pretreatments with fumonisins initiate regenerative cell proliferation, loss of tumor necrosis factor alpha and promotion of tumorigenesis.12