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Introduction to Genomics
Published in Altuna Akalin, Computational Genomics with R, 2020
The majority of splicing repressors are heterogeneous nuclear ribonucleoproteins (hnRNPs). If splicing repressor protein bind silencer elements, they reduce the chance of a nearby site being used as a splice junction. On the contrary, splicing enhancers are sites to which splicing activator proteins bind and binding on that region increases the probability that a nearby site will be used as a splice junction (Wang and Burge, 2008). Most of the activator proteins that bind to splicing enhancers are members of the SR protein family. Such proteins can recognize specific RNA recognition motifs. By regulating splicing exons can be skipped or included, which creates protein diversity (Wang and Burge, 2008).
Cardiac Subcellular Function During Diabetes
Published in Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla, Heart Dysfunction in Diabetes, 2019
Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla
Gross alterations in SR protein composition were not apparent during diabetes.23 Although some changes in lipid composition of the microsomal fraction were evident, these alterations were not dramatic and were unlikely to fully explain the membrane dysfunction. Regulation of Ca2+ transport by various phosphorylation mechanisms did not appear to be altered in in vitro measurements with cardiac SR membranes from diabetic animals.27
Receptors and Signal Transduction Pathways Involved in Autonomic Responses
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
The role of DAG and activation of PKC in the contractile responses of smooth muscle to a1-adrenoceptor and muscarinic M3 receptor stimulation is less certain than for IP3. To understand the possible effects of PKC activation, it is necessary to review the role of Ca2+ in smooth muscle contraction. An elevation of cytoplasmic free Ca2+ causes activation of the smooth muscle myofilaments involving actomyosin cross-bridge cycling (see Chapter 1). The cytoplasmic Ca2+ is believed to complex with the intracellular protein, calmodulin. This complex then activates myosin light chain kinase (MLCK), which in turn phosphorylates myosin light chain, the degree of which controls the actin-myosin cross-linkage and thus the smootii muscle contraction (Timmermans & Thoolen 1987). Intracellular Ca2+ levels are raised by influx of extracellular Ca2+ through voltage-operated (VOCs) or receptor-operated (ROCs) Ca2+ channels and by release of intracellular Ca2+ stored in the SR. The release of Ca2+ from the SR is induced by opening of IP3-sensitive channels (see above) and through Ca2+-activated channels that open when the cytoplasmic Ca2+ levels are raised, for example, by Ca2+ influx (Figure 13.4). The return of Ca2+ to the SR is driven by Ca2+,Mg2+-ATPase which appears to be linked to the SR protein, phospholamban. Phosphorylation of phospholamban by elevated levels of cAMP or cGMP increases Ca2+,Mg2+-ATPase activity and removal of Ca2+ from the cytoplasm. This, in part, explains the relaxation of smooth muscle by agents that raise levels of these two cyclic nucleotides (β2 agonists and NO, respectively) (Giembycz & Raeburn 1991) (see later).
Characterization of the IVS-II-821 (A>C) (HBB: c.316-30A>C) Mutation in a β-Thalassemia Phenotype in Iran
Published in Hemoglobin, 2019
Azam Azimi, Parham Nejati, Soosan Tahmasebi, Sasan Alimoradi, Reza Alibakhshi
Regarding the confirmation of our hypothesis that this variant would alter the normal splicing processes of β-globin mRNA, we performed some bioinformatic analyses on reference and mutated sequences. Based on these bioinformatic analyses, two new ESE motifs as new recognition sites for SRP40 and SC35 were predicted in mutated sequence (CTAATCC and TAATCCTG, respectively for these two proteins) (Figure 2). These two predicted SR protein recognition sites had relatively higher scores than the defined thresholds in both programs (SRP40 and SC35 scored 78.1 and 77.5, respectively). Other matrices of the HSF program, recognized two new sequences in the mutated sequence, ATCCTG and TCCTGT, as EIE and ESR, respectively [17,18]. According to our results, the bioinformatic analysis of HBB: c.316-90A>G and HBB: c.316-70C>G verified them to be the nearest pathogenic mutations to this variant [30]. We concluded that this putative variant created these regulatory elements in the mutated sequence of IVS-II of the HBB gene in the setting of potential flanking 5′ and 3′ splice sites. Therefore, it could abolish the normal splicing process due to incorporation of a cryptic exon into the pre-mRNA. Consequently, it leads to abnormal thalassemia phenotypes.
Prognostic significance of SRSF2 mutations in myelodysplastic syndromes and chronic myelomonocytic leukemia: a meta-analysis
Published in Hematology, 2018
Pourya Arbab Jafari, Hossein Ayatollahi, Ramin Sadeghi, Maryam Sheikhi, Amir Asghari
Serine/arginine-rich splicing factor 2 (SRSF2) gene is one of the representative candidates which is located on chromosome 17q25. Encoded SRSF2 protein belongs to the SR-protein family and the function of this protein is binding to RNA with a recognition motif to eliminate introns [9]. Somatic SRSF2 mutations have been identified more frequently in CMML and less in MDS patients. Many studies indicated the prognostic value of SRSF2 mutations in MDS and CMML cases [10–21]. However, with the high prevalence of SRSF2 mutations, the distinct role of SRSF2 in clinical impact has been controversial. Thol et al. reported SRSF2 mutations in 24 out of 193 individuals with MDS and found that these mutations are an unfavorable prognostic factor in MDS patients [10]. Kang et al. observed mutations in 13 out of 129 patients with MDS and demonstrated that SRSF2 mutations had no effect on MDS patients [13]. Ouyang et al. detected SRSF2 mutations in 14 patients out of 56 individuals with CMML and reported that the presence of SRSF2 mutations was correlated with shorter overall survival (OS) [21]. Patnaik et al. suggested that SRSF2 was frequently mutated in CMML cases and had no prognostic impact on patients [20]. Therefore, to clarify the prognostic effect of SRSF2 mutations in patients with MDS and CMML, this meta-analysis was aimed.
Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Nidhi Jyotsana, Michael Heuser
Post-translational modifications of splicing factors including phosphorylation and dephosphorylation via protein kinases and phosphatases also affect alternative splice site selection. Phosphorylation of SR protein SRp38 switches this general splice suppressor into a sequence-dependent splicing activator [79]. Phosphorylation of PTB on Ser16 via protein kinase A leads to its translocation to cytoplasm, affecting alternative splicing patterns of pre-mRNA [80]. Mutant non-functional forms of the SR-kinase family proteins SRSF protein kinase 1 (SRPK1) and CDC-like kinase CLK1-4 result in global inhibition of splicing [81,82]. Thus, dysregulation of spliceosome genes has broad consequences and may induce cancer pathogenesis and progression.