Regulation of gene expression by alternative untranslated regions

Hughes, Tom

doi:10.1016/j.tig.2006.01.001

Cited by 298 publications

(235 citation statements)

References 26 publications

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“…The preference for longer PTCH1b transcripts could be one form of spatio-temporal regulation of translation, utilized when lower and more tightly regulated levels of PTC1-L are needed. 55 Characteristics and presence of different cis-regulatory elements led us to hypothesize that PTCH1b 5'UTR in general affect the efficiency of cap-dependent initiation of PTC1-L translation. 56 This might even anticipate that PTCH1b 5'UTR possesses a capability to initiate cap-independent, an internal ribosome entry site-driven translation of PTC1-L. 57,58 Although the number of reports on cellular IRESes is increasing, their existence still raises skepticism and is often subject of scientific debates, mainly due to concerns about the lack of unambiguous experimental verifications.…”

Section: Discussionmentioning

confidence: 99%

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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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 that fine-tuning systems of protein patched homolog 1 (PTC1) levels exist to properly regulate the pathway. Given the role of 5' untranslated region (5'UTR) in protein expression, our aim was to thoroughly explore cis-regulatory elements in the 5'UTR of PTCH1 transcript 1b. The (CGG) n polymorphism was the main potential regulatory element studied so far but with inconsistent results and no clear association between repeat number and disease risk. Using luciferase reporter constructs in human cell lines here we show that the number of CGG repeats has no strong impact on gene expression, both at mRNA and protein levels. We observed variability in the length of 5'UTR and changes in abundance of the associated transcripts after pathway activation. We show that upstream AUG codons (uAUGs) present only in longer 5'UTRs could negatively regulate the amount of PTC1 isoform L (PTC1-L). The existence of an internal ribosome entry site (IRES) observed using different approaches and mapped in the region comprising the CGG repeats, would counteract the effect of the uAUGs and enable synthesis of PTC1-L under stressful conditions, such as during hypoxia. Higher relative translation efficiency of PTCH1b mRNA in HEK 293T cultured hypoxia was observed by polysomal profiling and Western blot analyses. All our results point to an exceptionally complex and so far unexplored role of 5'UTR PTCH1b cis-element features in the regulation of the Hedgehog-Gli signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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“…Since the analyses via in situ hybridization and single-cell or tissue-specific RT-PCR to reveal distinct transcript patterns are not established in Physcomitrella yet, it is not possible to clarify directly if PPM2 regulation is executed on the transcript level. However, it has been reported that many transcription factors are subject to translational control rather than transcriptional control via their 5′ UTR, where different mechanisms have been described that lead to stalling or dissociation of scanning ribosomes (Hughes, 2006). Therefore, a structural analysis of the PPM2 5′ UTR was performed to investigate its potential role in translational regulation.…”

Section: Alternative Splicing Of the Ppm2 5′ Utrmentioning

confidence: 99%

The MADS-domain protein PPM2 preferentially occurs in gametangia and sporophytes of the moss Physcomitrella patens

Quodt

Faigl

Saedler

et al. 2007

Gene

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To date, the function of MADS-domain transcription factors in non-seed plants remains largely elusive, although a number of genes have been isolated and characterized from a variety of species. In our study we analyzed PPM2, a classical MIKC-type MADS-box gene from the moss Physcomitrella patens, taking advantage of the unique technical properties Physcomitrella offers in terms of efficient homologous recombination. We determined mRNA and protein distribution and performed targeted disruption of the genomic locus for functional analysis of PPM2. Despite weak ubiquitous expression, PPM2 protein is mostly found in male and female gametangia and basal parts of developing sporophytes. Therefore, PPM2 seems to function in both the haploid and the diploid phase of the moss life cycle. This situation reflects an evolutionary transition state of gene recruitment from an ancestral gametophytic generation into a derived sporophytic generation which became dominating in tracheophytes. However, a knock-out of the PPM2 gene did not cause visible phenotypical changes in the respective structures. The implications of our findings for the understanding of the evolutionary history of MADS-box transcription factors in plants are discussed.

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“…Alternative transcription initiation may regulate tissue-or time-dependent expression due to a different response to transcription factors or by epigenetic changes. Moreover, it may regulate protein function by variations that could be generated in the N-terminal region (Hughes, 2006).…”

Section: Introductionmentioning

confidence: 99%

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

et al. 2007

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Patched1 (PTCH1) is one of the key molecules involved in the Hedgehog (HH) signaling pathway and acts as the receptor of HH ligands. Additionally, PTCH1 inhibits the positive signal transductor Smoothened (SMO). Several PTCH1 splice variants are known but the functional differences among them are not clear. Here, we demonstrate the unique biological properties of the PTCH1 isoforms generated by alternative first exon usage. All isoforms examined worked as functional receptors of both Sonic HH and Desert HH. However, the signaling upregulated isoforms PTCH1-1B and -1C inhibited SMO and the pathway transcription factors glioma 1 (GLI1) and GLI2 to a higher extent than PTCH1-1 and -1Ckid. Moreover, in situ hybridizations allowed the detection of the Ptch1 isoforms in specific structures of the developing mouse embryo. Additionally, the differences in the N-terminal tail had a dramatic influence on the steady states of the proteins, with PTCH1-1B and -1C levels being significantly higher than PTCH1-1 and -1Ckid. This implies that the pronounced signaling inhibitory properties of PTCH1-1B and -1C may be mostly due to this high-protein expression rather than to intrinsic functional differences. Thus, our study supports a role of splicing variation and promoter choice for HH signaling regulation.

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Regulation of gene expression by alternative untranslated regions

Cited by 298 publications

References 26 publications

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

The MADS-domain protein PPM2 preferentially occurs in gametangia and sporophytes of the moss Physcomitrella patens

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

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