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    • Introduction RNA splicing occurs in the nucleus when noncodi

    2022-05-26

    Introduction RNA splicing occurs in the nucleus when noncoding sequences (introns) are removed from the pre-mRNA transcript and coding sequences (exons) are joined to form a mature mRNA [1,2]. This reaction is catalyzed by a multiprotein complex called spliceosome. The spliceosome consists of five small nuclear ribonucleoproteins (snRNPs) and over a 100 of other proteins [[3], [4], [5], [6]]. Alternative pre-mRNA splicing allows Candesartan mg to create protein isoforms possessing different or even opposite functions from a single gene. The strict control of alternatively spliced mRNA isoforms’ balance is needed throughout the different development stages or physiological conditions [7]. Splicing events are tissue-specific so they are important for cellular differentiation and development [8,9]. The selection of alternative splice sites can be regulated in different manners related to tissue specificity, developmental stage, physiological processes, sex determination and in response to various stress factors [[8], [9], [10]]. The biological responses to hypoxia involve induction of transcription of a network of target genes, a process that is coordinately regulated by hypoxia-inducible transcription factors (HIFs). HIFs are heterodimeric transcription factors of the bHLH family, comprised of oxygen dependent α- and a constitutively expressed β-subunits [11,12]. Until now, three oxygen-sensitive isoforms have been described (1α, 2α and 3α) in eukaryotic cells. The α-subunits function as oxygen sensors and their levels are rapidly up-regulated by cellular hypoxia or exposure to certain divalent cations like Co2+. The β-subunit is also known as the aryl hydrocarbon (dioxin) receptor (AhR) nuclear translocator protein (ARNT) [11,13]. Splicing machinery highly contributes to the cells’ ability to adapt to different altered cellular conditions [14,15]. A number of reports describe hypoxia induced changes in alternative pre-mRNA splicing patterns in cells. Pre-mRNA splicing of 16 different genes is changed in human umbilical vein endothelial cells, cultivated under hypoxia mimicking conditions [16]. In ventricular myocytes hypoxia induces an alternatively spliced variant of Bnip3 (BCL2/adenovirus E1B 19-kDa protein-interacting protein 3) pre-mRNA [17]. In DB-1 melanoma cells hypoxia induces production of the alternative splice isoform of PFKFB (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) mRNA [18]. Cancer cells often take advantage of this flexibility to produce proteins that promote their growth and survival [19]. Alternative splicing of the Fas receptor pre-mRNA provides potentially important means by which tumor cells can escape elimination by the immune system. The Fas protein (also known as CD95) is a widely expressed cell's surface receptor that binds the Fas ligand (FasL) [20]. In addition to producing the full-length mRNA, the Fas pre-mRNA can be alternatively spliced to produce a number of shorter products. Exon 6 skipping results in expression of the soluble isoform of Fas (sFas), which is secreted out of the cell [21,22]. Elevated production of sFas protein has been observed in a wide range of cancers [[23], [24], [25]]. As Fas pre-mRNA alternative splicing has the potential to play a role in the suppression of the anti-tumor immune response, its regulation has been extensively investigated [26] and several individual factors have been identified as regulators in normoxic cells [[27], [28], [29], [30], [31], [32], [33]]. It has been shown that the reduction of the cellular level of hnRNPA1 protein promotes Fas exon 6 skipping (i.e. sFas mRNA formation) in MDA-MB-231 and HCT 116 cells. Overexpression of this factor in the same cell lines increases exon 6 inclusion into mRNA in a minigene assay [34]. A decrease in SPF45 protein expression levels in SKOV-3 ovarian cancer and HeLa cells inhibits sFas mRNA isoform formation using a minigene assay [28,29]. Another proto-oncogene Rac1 is a Ras superfamily GTPase that cycles between an inactive GDP-bound and an active GTP-bound form. Rac1 protein plays a significant regulatory role specifically in cells’ motility, growth and survival [35,36]. Rac1 pre-mRNA is alternatively spliced to produce a Rac1b named mRNA isoform, which contains internal 57-nt exon 3b. This isoform shows striking tumor-specific expression pattern and is upregulated in metastatic sites [[37], [38], [39], [40]]. Rac1b protein has been subsequently implicated as a central player in a number of different signaling pathways, involving cell survival and tumorigenesis [[41], [42], [43], [44]].