Abstract:Inga (2015) Regulation of human PTCH1b expression by different 5' untranslated region cis-regulatory elements, RNA Biology, 12:3, 290-304, DOI: 10.1080/15476286.2015 PTCH1 gene codes for a 12-pass transmembrane receptor with a negative regulatory role in the Hedgehog-Gli signaling pathway. PTCH1 germline mutations cause Gorlin syndrome, a disorder characterized by developmental abnormalities and tumor susceptibility. The autosomal dominant inheritance, and the evidence for PTCH1 haploinsufficiency, suggests … Show more
“…At high cell density, the ratio of the ARPC2 to actin protein level increased statistically significantly by approximately 2-fold. This finding is in line with the hypothesis that IRES elements maintain efficient translation under stressful conditions, when regular cap-dependent translation is compromised [25][26][27][28]54]. The IRES activity was further strengthened when we used rapamycin to modulate endogenous translation.…”
The 5ʹ-UTR of the actin-related protein 2/3 complex subunit 2 (ARPC2) mRNA exists in two variants. Using a bicistronic reporter construct, the present study demonstrates that the longer variant of the 5ʹ-UTR harbours an internal ribosome entry site (IRES) which is lacking in the shorter one. Multiple control assays confirmed that only this variant promotes cap-independent translation. Furthermore, it includes a guanine-rich region that is capable of forming a guanine-quadruplex (G-quadruplex) structure which was found to contribute to the IRES activity. To investigate the cellular function of the IRES element, we determined the expression level of ARPC2 at various cell densities. At high cell density, the relative ARPC2 protein level increases, supporting the presumed function of IRES elements in driving the expression of certain genes under stressful conditions that compromise cap-dependent translation. Based on chemical probing experiments and computer-based predictions, we propose a structural model of the IRES element, which includes the G-quadruplex motif exposed from the central stemloop element. Taken together, our study describes the functional relevance of two alternative 5ʹ-UTR splice variants of the ARPC2 mRNA, one of which contains an IRES element with a G-quadruplex as a central motif, promoting translation under stressful cellular conditions ARTICLE HISTORY
“…At high cell density, the ratio of the ARPC2 to actin protein level increased statistically significantly by approximately 2-fold. This finding is in line with the hypothesis that IRES elements maintain efficient translation under stressful conditions, when regular cap-dependent translation is compromised [25][26][27][28]54]. The IRES activity was further strengthened when we used rapamycin to modulate endogenous translation.…”
The 5ʹ-UTR of the actin-related protein 2/3 complex subunit 2 (ARPC2) mRNA exists in two variants. Using a bicistronic reporter construct, the present study demonstrates that the longer variant of the 5ʹ-UTR harbours an internal ribosome entry site (IRES) which is lacking in the shorter one. Multiple control assays confirmed that only this variant promotes cap-independent translation. Furthermore, it includes a guanine-rich region that is capable of forming a guanine-quadruplex (G-quadruplex) structure which was found to contribute to the IRES activity. To investigate the cellular function of the IRES element, we determined the expression level of ARPC2 at various cell densities. At high cell density, the relative ARPC2 protein level increases, supporting the presumed function of IRES elements in driving the expression of certain genes under stressful conditions that compromise cap-dependent translation. Based on chemical probing experiments and computer-based predictions, we propose a structural model of the IRES element, which includes the G-quadruplex motif exposed from the central stemloop element. Taken together, our study describes the functional relevance of two alternative 5ʹ-UTR splice variants of the ARPC2 mRNA, one of which contains an IRES element with a G-quadruplex as a central motif, promoting translation under stressful cellular conditions ARTICLE HISTORY
“…Due to the capacity of A2M to disrupt inflammatory cascade, its high expression could be explained by the marked pro-inflammatory profile of Gorlin’s patient fibroblasts. Human hedgehog interacting protein (HHIP), a negative regulator of Hh signalling frequently underexpressed in several tumours [ 57 , 58 , 59 , 60 ], showed an extremely high level of expression in NBCCS-HFs suggesting a compensatory mechanism acting on Hh pathway. Moreover, our data confirmed previous studies [ 49 , 50 , 51 ] demonstrating high level of matrix metalloproteinase 1 (MMP1) and of Secreted Frizzled Related Protein 2 (SFRP2), a soluble modulator of Wnt signalling.…”
Activating mutations in the Hh pathway underlies the development of sporadic and familial skin BCC. For these oncogenic proliferations displaying ligand-independent activation of the intracellular pathway, two molecules have been approved for therapeutic purposes: vismodegib and sonidegib. Improper Hh signalling occurs in many human tumours also via a paracrine mechanism (ligand-dependent) in which the secretion of Hh ligands by stromal cells support tumour growth. On the other hand, the mobilization of neoplastic stroma by cancer cells is sustained by the activation of Hh signalling in surrounding fibroblasts suggesting a central role of this bidirectional crosstalk in carcinogenesis. Additionally, loss-of-function mutations in the PTCH1 gene in the context of NBCCS, an autosomal dominant disorder predisposing to multiple BCCs, determine tumour permissive phenotypes in dermal fibroblasts. Here, profiling syndromic and BCC-associated fibroblasts unveiled an extraordinary similarity characterized by overexpression of several Hh target genes and a marked pro-inflammatory outline. Both cell types exposed to Hh inhibitors displayed reversion of the tumour-prone phenotype. Under vismodegib and sonidegib treatment, the Wnt/β-catenin pathway, frequently over-active in tumour stroma, resulted down-regulated by pAKT-GSK3β axis and consequent increase of β-catenin turnover. Overall, this study demonstrated that vismodegib and sonidegib impacting on fibroblast tumour supportive functions might be considered in therapy for BCC independently to the mutation status of Hh components in neoplastic cells.
“…6C), but had alterations in the N-terminal sequence. AS producing changes in the 5′ UTR of XTH could also affect transcript stability, translation efficiency and/or subcellular localization 46,47 .Figure 7RT-PCR analysis of differentially expressed sugarcane gene isoforms. Alternative splicing in selected sugarcane genes was analyzed using RT-PCR.…”
Alternative splicing (AS) promotes transcriptome and proteome diversity during growth, development, and stress responses in eukaryotes. Genome-wide studies of AS in sugarcane (
Saccharum
spp.) are lacking, mainly due to the absence of a high-quality sequenced reference genome, sugarcane’s large, complex genome, and the variable chromosome numbers and polyploidy of sugarcane cultivars. Here, we analyzed changes in the sugarcane isoform-level transcriptome and AS landscape during infection with the smut fungus (
Sporisorium scitamineum
) using a hybrid approach involving
Sorghum bicolor
reference-based and Trinity
de novo
mapping tools. In total, this analysis detected 16,039 and 15,379 transcripts (≥2 FPKM) at 5 and 200 days after infection, respectively. A conservative estimate of isoform-level expression suggested that approximately 5,000 (14%) sugarcane genes undergo AS. Differential expression analysis of the alternatively spliced genes in healthy and smut-infected sugarcane revealed 896 AS events modulated at different stages of infection. Gene family and gene ontology functional enrichment analysis of the differentially spliced genes revealed overrepresentation of functional categories related to the cell wall, defense, and redox homeostasis pathways. Our study provides novel insight into the AS landscape of sugarcane during smut disease interactions.
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