Silencers regulate both constitutive and alternative splicing events in mammals

Pozzoli, Uberto; Sironi, Manuela

doi:10.1007/s00018-005-5030-6

Cited by 63 publications

(46 citation statements)

References 177 publications

(215 reference statements)

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“…However, our results clearly demonstrate that Pirh2C exists naturally, perhaps through "leaky" utilization of donor site 2. A number of factors could influence the differential splicing of Pirh2C, such as lack of definition between the two canonical donor sites, or it could be due to comparatively weak elements within Pirh2 exons or introns that provide information to the mRNA splicing machinery (48). Further in-depth studies are also needed to elucidate the molecular mechanisms underlying the generation of this isoform.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Two Novel Isoforms of Pirh2 Ubiquitin Ligase That Negatively Regulate p53 Independent of RING Finger Domains

Corcoran

Montalbano

Sun

et al. 2009

Journal of Biological Chemistry

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Pirh2 is a newly identified E3 ubiquitin ligase known to inhibit tumor suppressor p53 function via ubiquitination and proteasomal degradation. We have identified two novel Pirh2 splice variants that encode different Pirh2 isoforms and named these Pirh2B and Pirh2C. Accordingly, the full-length protein is now classified as isoform Pirh2A. The central region of Pirh2 harbors a RING finger domain that is critical for its ubiquitin ligase function. The Pirh2B isoform lacks amino acids 171-179, whereas Pirh2C is missing C-terminal amino acids 180 -261, which for each isoform results in a RING domain deletion and the abrogation of ubiquitin ligase activity. Our findings further indicate that the Pirh2B isoform but not the Pirh2C isoform is capable of binding to Pirh2A, suggesting that the C-terminal region absent in Pirh2C is critical for Pirh2-Pirh2 interactions. Similar to Pirh2A, both Pirh2B and Pirh2C interact with p53; however, interactions between p53 and Pirh2B appear stronger than those between p53 and Pirh2C. Interestingly, although both Pirh2B and Pirh2C are not able to promote in vitro p53 ubiquitination, both are capable of negatively regulating p53 protein stability and promoting the intracellular ubiquitination of p53. Furthermore, like Pirh2A, both isoforms are able to inhibit p53 transcriptional activity. We have also for the first time demonstrated that Pirh2A as well as the novel isoforms also interact directly with MDM2 within a region encompassing MDM2 acidic and zinc finger domains. It is therefore possible that Pirh2A and the novel Pirh2 isoforms identified in this study may also modulate p53 function by engaging MDM2.The tumor suppressor p53 has been implicated in a growing number of cellular processes, the most recognized of these being the initiation of signaling cascades leading to growth arrest and apoptosis (1). A large body of evidence supports the notion that p53 is capable of regulating these pathways via distinct mechanisms. It is becoming clear that p53 probably exerts its antiproliferative effects through both its well established transcription factor function as well as a transcription-independent role at the mitochondrion (1-3).Given its potent capacity to control cell fate, p53 in normal cells is held in check at multiple, often interrelated levels, including regulation of p53 protein stability, subcellular localization, and transcriptional activity. It is now well understood that p53 ubiquitination and subsequent proteasomal degradation is one of the principal mechanisms controlling these processes (4 -6). The RING domain containing ubiquitin ligase MDM2 was the first non-viral protein found to be responsible for the ubiquitin-dependent targeting of p53 for proteolysis (7,8). The importance of MDM2 in abrogating p53 function was illustrated in an embryonic lethal MDM2(Ϫ/Ϫ) mouse model in which lethality can be attributed to uncontrolled p53 activity and is rescued by p53 deletion (9, 10).Adding complexity to the once clear role of MDM2 in p53 ubiquitination is the recent discovery...

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Two Novel Isoforms of Pirh2 Ubiquitin Ligase That Negatively Regulate p53 Independent of RING Finger Domains

Corcoran

Montalbano

Sun

et al. 2009

Journal of Biological Chemistry

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“…ESSs are often bound by splicing repressors of the hnRNP class, a diverse group of proteins containing one or more RNA-binding domains and sometimes splicing inhibitory domains such as glycine-rich motifs (Pozzoli and Sironi 2005). hnRNPs function by a wide variety of mechanisms.…”

Section: Exonic Splicing Enhancers and Silencersmentioning

confidence: 99%

Splicing regulation: From a parts list of regulatory elements to an integrated splicing code

Wang¹,

Burge²

2008

RNA

901

761

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Alternative splicing of pre-mRNAs is a major contributor to both proteomic diversity and control of gene expression levels. Splicing is tightly regulated in different tissues and developmental stages, and its disruption can lead to a wide range of human diseases. An important long-term goal in the splicing field is to determine a set of rules or ''code'' for splicing that will enable prediction of the splicing pattern of any primary transcript from its sequence. Outside of the core splice site motifs, the bulk of the information required for splicing is thought to be contained in exonic and intronic cis-regulatory elements that function by recruitment of sequence-specific RNA-binding protein factors that either activate or repress the use of adjacent splice sites. Here, we summarize the current state of knowledge of splicing cis-regulatory elements and their context-dependent effects on splicing, emphasizing recent global/genome-wide studies and open questions.Keywords: context dependence; pre-mRNA splicing; splicing code; splicing factor; splicing regulation PRE-MRNA SPLICING Because human genes typically contain multiple introns, the process of pre-mRNA splicing is an essential step in the expression of most genes. A majority of human genes undergo alternative splicing (AS), generating multiple splicing isoforms containing different combinations of exons (Johnson et al. 2003). The effects of AS on protein products can be dramatic, e.g., producing soluble versus membranebound forms of the Fas receptor that have opposing effects on apoptosis (Cascino et al. 1995), or producing isoforms of the Drosophila fruitless protein that act to specify sexual orientation (Demir and Dickson 2005). The major forms of AS are summarized in Figure 1A. Splicing regulation has been comprehensively described in several recent reviews (Black 2003;Konarska and Query 2005;Matlin et al. 2005;Blencowe 2006;House and Lynch 2008). Here, we briefly summarize some aspects of splicing specificity and regulation before turning to our main topic of splicing regulatory elements and the rules governing their activity.The sequential phosphodiester transfer reactions involved in splicing are catalyzed by large ribonucleoprotein complexes known as spliceosomes. Containing more than 100 core proteins and five small nuclear RNAs (snRNAs U1, U2, U4, U5, and U6), spliceosomes may be the most complex machines in the cell (Zhou et al. 2002;Jurica and Moore 2003;Nilsen 2003). In addition to these core factors, additional regulatory proteins participate in the splicing of particular pre-mRNAs. Splicing of most introns is thought to occur cotranscriptionally with fairly extensive interactions between splicing factors and the core transcription machinery ( CORE SPLICING SIGNALSThree sites, the 59 splice site (59ss), the 39 splice site (39ss), and the branch point sequence (BPS), participate in the splicing reaction and are present in every intron, and thus are known as the core splicing signals. These signals are recognized multiple times during spl...

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“…[15][16][17][18] An interesting switch in the abundance of the splicing regulator polypyrimidine tract binding protein (PTB) to its neuronal counterpart nPTB represents an important trigger in neuronal their interactors. 11,12 In general, binding sites for SR proteins are more frequent in true exons, and hnRNP binding sites are more often found in introns.…”

Section: The Importance Of Exon Definitionmentioning

confidence: 99%

“…Moreover additional proteins not belonging to these two groups, such as proteins of the CELF/ Bruno-like family, 11,13 can act both as enhancers or modulators of splicing. In the end, the definition of an exon and hence its inclusion in the mature mRNA is the composite result of the sequences and relative positions of splicing signals (SS and BP), enhancers and silencers, the amounts of enhancing and repressing transacting factors and their interaction with each other as well as with components of the basic splicing machinery.…”

Section: The Importance Of Exon Definitionmentioning

confidence: 99%