Genetic Susceptibility to Colorectal Cancer
Jim Cassidy, Patrick Johnston, Eric Van Cutsem in Colorectal Cancer, 2006
The function of the APC gene product is the focus of much research interest and the complexities of the cellular role of APC have yet to be fully understood. The APC protein is expressed in epithelial cells in the upper portions of the colonic crypts, suggesting involvement in colonocyte maturation (100–101). Several functional domains are revealed in the protein sequence including the N-terminal homodimerization sequences, as well as numerous other cellular processes such as cellular adhesion, cell-cycle regulation, apoptosis, differentiation, and intracellular signal transduction. The central region of the protein contains β-catenin binding and regulatory domains as well as binding domains for the axin family of proteins. APC appears to influence cellular adhesion by affecting the interaction between catenins and E-cadherin, thus promoting the shedding and migration of epithelial cells. In conjunction with other proteins, axin, glycogen synthase kinase 3β (GSK), and other GSK binding proteins, APC plays a critical role in intra-cellular communication by modulating the levels of β-catenin-dependent transcription (102). β-catenin is an important transcription factor for oncogenic proteins such as cyclin D1 and c-myc (103). The pivotal role of abnormalities in the wnt signaling pathway in colorectal tumorigenesis is exemplified by the identification of somatic mutations in many of the components, such as APC, β-catenin, and axin, with somatic APC mutations being identified in ~85% of all colorectal tumors (104).
Definition of an allergen (immunobiology)
Richard F. Lockey, Dennis K. Ledford in Allergens and Allergen Immunotherapy, 2020
An operationally defined allergen shows immunogenicity (a capacity to establish a state of sensitivity and/or stimulate the formation of corresponding antibody) and also reacts specifically with those antibodies [1]. Typically, proteins are more immunogenic than carbohydrates. Because of their size, haptens (low molecular weight compounds, such as drugs) are not immunogenic in and of themselves but do possess antigenic epitopes [1]. In the proper context, such as may exist after a hapten has covalently bound to a larger protein, the hapten-protein complex is taken up and processed by an APC. The allergenic epitope of the hapten-protein complex is presented in the context of a MHC (cell surface antigens of the major histocompatibility complex). This results in the production of antibody specific for that allergenic epitope. In atopic immune responses, the antigen eliciting an immune response is termed an allergen. In order for the immune system to respond to an allergen, the allergen must be recognized as foreign. Thus, a molecule might function as an allergen in one organism but not in another simply because one organism recognizes it as foreign and the other does not. This chapter is primarily concerned with molecules recognized as antigens by the humoral system of humans, specifically those with the ability to induce an allergic, or IgE-mediated, response.
Wnt signaling in spermatogenesis and male infertility
Rajender Singh in Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Canonical Wnt signaling involves the accumulation of β-catenin in the cytoplasm and its subsequent translocation into the nucleus (Figure 9.1). When there is no ligand, a destruction complex is formed, which consists of a group of proteins, mainly Axin, adenomatous polyposis coli (APC), casein kinase 1α (CK1α) and glycogen synthase kinase 3 (GSK-3). β-Vatenin is phosphorylated by casein kinase 1α (CK1α) at Ser45, followed by phosphorylation by GSK-3 at Thr41, Ser37 and Ser33. Phosphorylated β-catenin becomes ubiquitylated and is targeted for proteasomal degradation (20). On binding of Wnt to a receptor complex, which is composed of members of the Frizzled (Fz) family of seven-transmembrane, low-density lipoprotein receptor-related protein (LRP), serpentine receptors, the Axin-APC-CK1α-GSK-3 complex is inhibited. This inhibition stops phosphorylation of β-catenin by CK1α and GSK-3, further inhibiting its proteasomal degradation. This unphosphorylated β-catenin accumulates in the cytoplasm and is translocated into the nucleus where it interacts with the T-cell-specific transcription factor/lymphoid enhancer-binding factor 1 (TCF/LEF) family of transcription factors and regulates the expression of the target genes (21).
Bioinformatic analysis of the clinicopathological and prognostic significance of oocyte-arresting BTG4 mRNA expression in gynecological cancers
Published in Journal of Obstetrics and Gynaecology, 2023
Hua-chuan Zheng, Hang Xue, Cong-yu Zhang, Rui Zhang
Räty et al. (2011) identified BTG4 as a potential candidate for oocyte developmental competence, as a secreted acidic protein rich in cysteine for cumulus cell expansion. Moreover, Liu et al. (2021) reported that a novel homozygous missense variant in BTG4 causes zygotic cleavage failure and female infertility. Meanwhile, Chu et al. (2012) found that BTG4 had a higher mRNA level in oocytes treated with FSH than in those produced through the natural cycle. Furthermore, Pasternak et al. (2016) demonstrated that the BTG4-CAF1 complex safeguarded metaphase II arrest in mammalian eggs by deadenylating maternal mRNAs. BTG4-depleted eggs progressed into anaphase II spontaneously before fertilization. BTG4 prevented the progression into anaphase by ensuring that the anaphase-promoting complex/cyclosome (APC/C) was completely inhibited during the arrest. These findings indicate that BTG4 may block the cycle progression of oocytes or eggs.
Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2018
Siqing Fu, Yudong Wang, Khandan Keyomarsi, Funda Meric-Bernstein
Wee1 has emerged as a key player in regulating histone synthesis by phosphorylating histone H2B at Y37 in the nucleosomes found upstream of the histone gene cluster to suppress histone transcription in late S phase and inhibit anaphase onset [28]. Wee1 kinase acts as a mitotic gatekeeper and an epigenetic modifier, providing a direct link between epigenetic modulation and cell cycle progression [29]. Loss of expression or inhibition of Wee1 kinase abrogates H2B Y37 phosphorylation with a concomitant increase in histone transcription by reversing the process to recruit nuclear protein mapped to the ATM locus (NPAT, p220) and RNA polymerase II [30]. Thus, Wee1 kinase acts as a hub for regulating chromatin integrity through blocking replication initiation, G2-M transition, and histone transcription to allow cells to maintain DNA replication fidelity and chromatin integrity. The anaphase-promoting complex/cyclosome (APC/C), a multi-subunit member of the RING finger family of ubiquitin ligase, mediates Wee1 degradation to allow mitotic progression, since Wee1 delays this progression to maintain genomic integrity [18].
Impact of copper oxide particle dissolution on lung epithelial cell toxicity: response characterization using global transcriptional analysis
Published in Nanotoxicology, 2021
Andrey Boyadzhiev, Mary-Luyza Avramescu, Dongmei Wu, Andrew Williams, Pat Rasmussen, Sabina Halappanavar
All samples which showed a cumulative DEG count <40 were used for GO gene set enrichment analysis (molecular function, biological process, and cellular compartment) using ClueGO. From all samples analyzed, only FE1 cells exposed to 25µg/mL CuO MPs at the 2h timepoint had significantly enriched GO terms (Supplementary Figure S4). The enriched categories were represented by the downregulated DEGs implicated in the biological processes ‘regulation of meiotic cell cycle’ [GO:0051445] and ‘anaphase-promoting complex-dependent catabolic process’ [GO:0031145], as well as the cellular components ‘nuclear ubiquitin ligase complex’ [GO:0000152] and ‘anaphase-promoting complex’ [GO:0005680].
Related Knowledge Centers
- Conserved Sequence
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- Proteolysis
- Ubiquitin
- Ubiquitin Ligase
- Cell Cycle
- Ring Finger Domain
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