Inhibitory Smad7: Emerging Roles in Health and Disease

Briones-Orta, Marco A.; Tecalco-Cruz, Ángeles C.; Sosa-Garrocho, Marcela; Caligaris, Cassandre; Macı́as-Silva, Marina

doi:10.2174/1874-470211104020141

Cited by 53 publications

(46 citation statements)

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“…We also tested whether overexpression of UPF1 had the reciprocal affect, but observed no change in Smad7 mRNA levels (Figure S3C), implying that UPF1 is not rate limiting for NMD in P19 cells. Since there is evidence that SMAD7 not only promotes neural differentiation but also inhibits cell proliferation (Briones-Orta et al, 2011), we also assessed whether SMAD7 has a role in NMD’s pro-proliferation function. We found that knockdown of SMAD7 did not significantly rescue the effect of NMD on cellular proliferation in P19 cells (Figures S3D, S3E, and S3F), suggesting that NMD regulates proliferation independently of SMAD7.…”

Section: Resultsmentioning

confidence: 99%

Posttranscriptional Control of the Stem Cell and Neurogenic Programs by the Nonsense-Mediated RNA Decay Pathway

et al. 2014

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SUMMARY The mechanisms dictating whether a cell proliferates or differentiates have undergone intense scrutiny but remain poorly understood. Here, we report that a central component in the nonsense-mediated RNA decay (NMD) pathway—UPF1—plays a key role in this decision by promoting the proliferative, undifferentiated cell state. UPF1 acts, in part, by destabilizing the NMD substrate encoding the TGFβ inhibitor, SMAD7, and stimulating TGFβ signaling. UPF1 also promotes the decay of mRNAs encoding many other proteins that oppose the proliferative, undifferentiated cell state. Neural differentiation is triggered when NMD is downregulated by neurally expressed microRNAs (miRNAs). This UPF1-miRNA circuitry is highly conserved and harbors negative feedback loops that act as a molecular switch. Our results suggest that the NMD RNA decay pathway collaborates with the TGF-β signaling pathway to lock-in the stem-like state, a cellular state that is stably reversed when neural differentiation signals that induce NMD-repressive miRNAs are received.

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Section: Resultsmentioning

confidence: 99%

Posttranscriptional Control of the Stem Cell and Neurogenic Programs by the Nonsense-Mediated RNA Decay Pathway

et al. 2014

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“…Smad7 is thought to inhibit TGF-b signaling by competing with Smad2/3 for binding to the type I receptor, enhancing ubiquitination of Smad complexes, and inhibiting Smad/DNA complexes in the nucleus (26). Specific roles of Smad7 may be cell and stage specific (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Smad7 antagonizes TGF-b signaling through multiple mechanisms, playing pivotal roles in embryonic development and adult homoeostasis (10,11). Altered expression of Smad7 is associated with several human disease processes, including cancer, tissue fibrosis, and inflammatory diseases (12). Though Smad7 mRNA has been localized in mouse oocytes (13), this is the first report of localization, regulation, and function of Smad7 in granulosa cells.…”

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confidence: 87%

Smad7 is a transforming growth factor-beta–inducible mediator of apoptosis in granulosa cells

Quezada

Wang

Hoang

et al. 2012

Fertility and Sterility

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“…143,144 Mongersen is an oral antisense oligonucleotide that specifically binds to SMAD7 messenger RNA and prevents its transcription by causing RNase-mediated degradation, in turn upregulating TGF-β1 signaling. There was considerable interest in mongersen after a phase 2 study demonstrated markedly superior clinical outcomes relative to placebo though no endoscopic outcomes were assessed 145 ; a later study assessing endoscopic outcomes in 63 active CD at a variety of treatment durations showed endoscopic improvement in 37%.…”

Section: What Is On the Horizonmentioning

confidence: 99%

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

et al. 2018

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The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.

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Inhibitory Smad7: Emerging Roles in Health and Disease

Cited by 53 publications

References 0 publications

Posttranscriptional Control of the Stem Cell and Neurogenic Programs by the Nonsense-Mediated RNA Decay Pathway

Posttranscriptional Control of the Stem Cell and Neurogenic Programs by the Nonsense-Mediated RNA Decay Pathway

Smad7 is a transforming growth factor-beta–inducible mediator of apoptosis in granulosa cells

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

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