Alternative Splicing of Brain-Specific PTB Defines a Tissue-Specific Isoform Pattern That Predicts Distinct Functional Roles

Rahman, Lambratu; Bliskovski, Valery; Reinhold, William C.; Zajac-Kaye, Maria

doi:10.1006/geno.2002.6826

Cited by 39 publications

(31 citation statements)

References 26 publications

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“…67 Consequently, when PTB levels are high, PTB production is slowed by targeting PTB transcripts for NMD and when PTB levels are low, production is accelerated by reducing the proportion of transcripts that are degraded. 67,69,70 A similar autoregulatory process has been reported for members of a family of splicing factors known as SR proteins. Overexpression of the SR protein SC35 upregulates the splicing of its own NMD-targeted isoform to reduce protein production.…”

Section: Autoregulatory Unproductive Splicingsupporting

confidence: 59%

The Coupling of Alternative Splicing and Nonsense-Mediated mRNA Decay

Lareau¹,

Brooks²,

Soergel³

et al. 2007

Advances in Experimental Medicine and Biology

208

192

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M ost human genes exhibit alternative splicing, but not all alternatively spliced transcripts produce functional proteins. Computational and experimental results indicate that a substantial fraction of alternative splicing events in humans result in mRNA isoforms that harbor a premature termination codon (PTC). These transcripts are predicted to be degraded by the nonsense-mediated mRNA decay (NMD) pathway. One explanation for the abundance of PTC-containing isoforms is that they represent splicing errors that are identified and degraded by the NMD pathway. Another potential explanation for this startling observation is that cells may link alternative splicing and NMD to regulate the abundance of mRNA transcripts. This mechanism, which we call "Regulated Unproductive Splicing and Translation" (RUST), has been experimentally shown to regulate expression of a wide variety of genes in many organisms from yeast to human. It is frequently employed for autoregulation of proteins that affect the splicing process itself. Thus, alternative splicing and NMD act together to play an important role in regulating gene expression.

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Section: Autoregulatory Unproductive Splicingsupporting

confidence: 59%

The Coupling of Alternative Splicing and Nonsense-Mediated mRNA Decay

Lareau¹,

Brooks²,

Soergel³

et al. 2007

Advances in Experimental Medicine and Biology

208

192

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“…TIA proteins may also regulate and autoregulate mRNA translation (Piecyk et al 2000), and whether that plays a role in their tissue-specific expression remains to be determined. PTB expression is also complex, with a number of different isoforms and cofactors (Wollerton et al 2001;Rahman et al 2002;Gromak et al 2003b). While there was no evidence in the current study for the tissue-specific expression of PTB 1 versus 4 splice variant isoforms, we cannot exclude the possibility that regulated expression of other PTB isoforms (e.g., the brain isoform), or binding cofactors, plays a role in the selection or suppression of alternative exons during the generation of smooth muscle phenotypic diversity.…”

Section: Wwwrnajournalorg 1731contrasting

confidence: 59%

Competition of PTB with TIA proteins for binding to a U-rich cis-element determines tissue-specific splicing of the myosin phosphatase targeting subunit 1

Shukla

Gatto–Konczak

Breathnach

et al. 2005

RNA

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A considerable amount of smooth muscle phenotypic diversity is generated by tissue-specific and developmentally regulated splicing of alternative exons. The control mechanisms are unknown. We are using a myosin phosphatase targeting subunit-1 (MYPT1) alternative exon as a model to investigate this question. In the present study, we show that the RNA binding proteins TIA and PTB function as antagonistic enhancers and suppressors of splicing of the alternative exon, respectively. Each functions through a single U-rich element, containing two UCUU motifs, just downstream of the alternative exon 5 0 splice site. Tissuespecific down-regulation of TIA protein in the perinatal period allows PTB to bind to the U-rich element and suppress splicing of the alternative exon as the visceral smooth muscle acquires the fast-phasic smooth muscle contractile phenotype. This provides a novel role for PTB in the tissue-specific regulation of splicing of alternative exons during the generation of smooth muscle phenotypic diversity.

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“…RNA transcription of protein-coding mRNAs observed from both strands of a locus (Labrador et al 2001), intron-containing genes (Levinson et al 1992;Conrad et al 2002), and transcripts with elongated or shortened exons coding for proteins with different functions (Rahman et al 2002) have all been previously observed. Consistent with these examples, the observed novel transcription found proximal to annotations may represent alternative exon isoforms (novel exons, extension of exons, or extensions of 5Ј-or 3Ј-UTRs) or distinct transcriptional units encoded on either the same strand or antisense strand to the characterized annotation.…”

Section: Transcriptome Of Chromosomes 21 and 22mentioning

confidence: 99%

Novel RNAs Identified From an In-Depth Analysis of the Transcriptome of Human Chromosomes 21 and 22

Kampa¹,

Cheng²,

Kapranov³

et al. 2004

Genome Res.

478

377

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In this report, we have achieved a richer view of the transcriptome for Chromosomes 21 and 22 by using high-density oligonucleotide arrays on cytosolic poly(A) + RNA. Conservatively, only 31.4% of the observed transcribed nucleotides correspond to well-annotated genes, whereas an additional 4.8% and 14.7% correspond to mRNAs and ESTs, respectively. Approximately 85% of the known exons were detected, and up to 21% of known genes have only a single isoform based on exon-skipping alternative expression. Overall, the expression of the well-characterized exons falls predominately into two categories, uniquely or ubiquitously expressed with an identifiable proportion of antisense transcripts. The remaining observed transcription (49.0%) was outside of any known annotation. These novel transcripts appear to be more cell-line-specific and have lower and less variation in expression than the well-characterized genes. Novel transcripts were further characterized based on their distance to annotations, transcript size, coding capacity, and identification as antisense to intronic sequences. By RT-PCR, 126 novel transcripts were independently verified, resulting in a 65% verification rate. These observations strongly support the argument for a re-evaluation of the total number of human genes and an alternative term for "gene" to encompass these growing, novel classes of RNA transcripts in the human genome.

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Alternative Splicing of Brain-Specific PTB Defines a Tissue-Specific Isoform Pattern That Predicts Distinct Functional Roles

Cited by 39 publications

References 26 publications

The Coupling of Alternative Splicing and Nonsense-Mediated mRNA Decay

The Coupling of Alternative Splicing and Nonsense-Mediated mRNA Decay

Competition of PTB with TIA proteins for binding to a U-rich cis-element determines tissue-specific splicing of the myosin phosphatase targeting subunit 1

Novel RNAs Identified From an In-Depth Analysis of the Transcriptome of Human Chromosomes 21 and 22

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