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Dyskeratosis Congenita
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Telomeres are coated by shelterin complex (telomere end protection/capping), an assembly of six associated proteins: (i) telomeric repeat binding factor 1 (TRF1; also known as TERF1) and (ii) TRF2 (also known as TERF2), (iii) TRF1-interacting nuclear factor 2 (TIN2), (iv) protection of telomeres (POT1), (v) TIN2-interacting protein 1 (TPP1) (also known as TINT1, PToP, and PIP1), and (vi) repressor/activator protein 1 (RAP1). RAP1 in mammals is involved in subtelomeric gene silencing and transcriptional regulation, and it also acts as an essential modulator of the nuclear factor-κB (NF-κB)-mediated pathway. Shelterin components play multiple roles in maintaining telomere length homeostasis by forming the T loops, preventing DNA damage response activation (DDRA), and recruiting the telomerase complex and modulating its activity. Although the regulation of shelterin components in stem cells and during nuclear reprogramming is still unexplored, some recent evidence suggests shelterin components as key factors in “stemness.” Some cases of premature aging in human syndromes have been linked to shelterin mutations, such as in TRF1, TRF2, and TIN2 (also known as TINF2).
Guanosine Triphosphate-Binding Proteins
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The number of Ras-related proteins identified in the last few years has been growing continuously. Multiple Ras-like guanine nucleotide-binding proteins have been detected in the plasma membranes of mouse fibroblasts.95 Some of these proteins may be involved in the transmission of mitogenic signals elicited by growth factors and other mitogenic signaling agents, but different Ras-related proteins may have different functions. The RaplA protein, also called Krev-1, is closely associated with the cytochrome b of human neutrophils, suggesting its involvement in the superoxide generating system.96 The RaplA protein is associated with the Golgi complex in rat and human cells.97 The putative effector domains shared between Ras and Rap proteins are functionally similar and interact with their respective GTPase-activating proteins.98 Expression of the rap-l gene is capable of suppressing ras-induced oncogenic transformation.99
The Molecular Genetics and Pathology of Renal Cell Carcinoma
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Maxine G. B. Tran, Tim O’Brien, Patrick H. Maxwell
Tuberous sclerosis. Tuberous sclerosis (TSC) is an autosomal dominant inherited syndrome characterized by seizures, mental retardation, and multiple hamartomas. Renal manifestations of TSC occur in over half of affected individuals and include angiomyolipoma (AML) in 85%, renal cysts in 45%, and renal cell carcinoma in 4% (119). AMLs are yellow and gray in color, and composed microscopically of adipocytes, sheets of smooth muscle and blood vessels. Two genes implicated in TSC have been identified, TSC1 and TSC2, and these have been mapped to chromosomes 9q34 (120) and 16p13.3, respectively (121). TSC1 encodes a protein called hamartin, which is involved in cell adhesion through the ezrin-radixinmoesin (ERNM) family of actin binding proteins (122), and TSC2 encodes tuberin, a GTPase activating protein for Rap1, a member of the Ras-related superfamily (123). Both AML and renal cysts are more common and numerous in patients with TSC2 mutations compared with TSC1 (119).
Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure
Published in Platelets, 2023
Mohammed M Jalal, Claire S Whyte, Fraser P Coxon, Nicola J Mutch
Platelets are finely tuned to modulate the response to mechanical injury or vascular breach. A crucial characteristic of platelet function is packaging and uptake of cargo that is subsequently released upon platelet activation. Membrane trafficking is also imperative to granule biogenesis and maturation in megakaryocytes and platelets.1 Small guanosine triphosphatases (GTPases)2,3 act as molecular switches cycling between an inactive GDP-bound’ form to an active “GTP-bound” form to regulate effector proteins which are crucial for trafficking events. GTPases localize to the cytosolic face of subcellular vesicles3 and modulate platelet function at several levels including regulation of platelet activation, integrin exposure4,5 and granule secretion.6,7 Rap1 GTPase belongs to the Ras family8 and exists as two isoforms Rap1a and Rap1b, which are encoded by separate genes but share approximately 95% sequence identity. Rap1a and Rap1b function in activation of the integrins αIIbβ3 and β1 and consequently impact on fibrinogen binding, aggregation, and cytoskeletal responses, including spreading.5,9 Rap1b is the predominant isoform Ras family member in platelets10 and plays additional roles over Rap1a in terms of α- granule secretion.4
Effects of inhibition of phosphodiesterase 3B in pancreatic islets on insulin secretion: a potential link with some stimulatory pathways
Published in Archives of Physiology and Biochemistry, 2021
Agnieszka Kilanowska, Tomasz Szkudelski
Sulfonylureas are widely used in type 2 diabetes to support insulin secretion if the function of β cells is partially retained. To study the potential link between sulfonylureas and inhibition of PDE3B on insulin secretion, pancreatic islets were exposed to glibenclamide and amrinone. Glibenclamide is an agonist for the SUR1 regulatory subunit, a sulfonylurea receptor of the KATP channel in the plasma membrane (Mikhailov et al.2002). Its presence leads to closure of this channel, resulting in membrane depolarization and opening of voltage-gated calcium channels. The increase in intracellular Ca2+ levels initiates the exocytosis of insulin granules. Moreover, the SUR1 subunit influences Epac2 protein which is directly activated by cAMP. Its presence leads to the activation of Rap1 (Ras-proximate-1 or Ras-related protein 1), also known as the small GTPase. Rap1 binds to PLC-ε, thus initiating a PIP2-dependent reaction. The above-described mechanisms lead to insulin exocytosis (Gloerich and Bos 2010 Dzhura et al.2011).
TGCnA: temporal gene coexpression network analysis using a low-rank plus sparse framework
Published in Journal of Applied Statistics, 2020
Jinyu Li, Yutong Lai, Chi Zhang, Qi Zhang
We first investigated the module conservation across time points. A new adjacency matrix was built whose edge weights were the proportion of total time points that this pair of genes were in the same module. We called a gene-gene interaction to be time-invariant if they were always in the same module. There were 1156 genes involved in such time-invariant connections, which led to a reduced adjacency matrix. Clustering based on its associated TOM distance matrix yielded 14 modules. KEGG enrichment of these modules showed that regulation of actin cytoskeleton, protein processing in endoplasmic reticulum (ER), Ras signaling pathway, MAPK signaling pathway, and Rap1 signaling pathway were enriched (FDR = 0.1 for each module). The regulation of the actin cytoskeleton pathway is critical for the development of the neural system, especially for neuronal migration [35]. Endoplasmic reticulum is related to various acute disorders and degenerative diseases of the brain [30]. The Ras and MAPK signaling pathways regulate many cell functions such as cell proliferation, survival and apoptosis. Rap1 pathway is important for Neuronal Progenitor Cell Differentiation [33]. Overall, these pathways encode fundamental cell functions that are expected to have strong effects at all time points, which could explain why these genes were always connected.