The CSL proteins, versatile transcription factors and context dependent corepressors of the notch signaling pathway

Contreras-Cornejo, Humberto; Saucedo-Correa, Germán; Oviedo-Boyso, Javier; Valdéz-Alarcón, Juan José; Baizabal-Aguirre, Víctor M.; Cajero-Juárez, Marcos; Bravo-Patiño, Alejandro

doi:10.1186/s13008-016-0025-2

Cited by 32 publications

(23 citation statements)

References 99 publications

(208 reference statements)

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“…Multiple mammalian “co-repressor” genes encode proteins that interact with Rbpj via CSL binding sites 56 . These genes are unrelated at the primary sequence level, but predicted to link Rbpj to HDAC machinery, and include Smrt/Ncor2 , Spen/Mint/Sharp , Fhl1b//KyoT2 , Rita , Skip , L3mbtl3 and Kdm1a/Lsd1 57 – 59 . Interestingly, Kdm1a/Lsd1 is expressed in the retina from E17-P15, and its pharmacologic inhibition in retinal explants induced an upregulation of bHLH factor expression 60 .…”

Section: Resultsmentioning

confidence: 99%

Rbpj direct regulation of Atoh7 transcription in the embryonic mouse retina

Miesfeld

Moon

Riesenberg

et al. 2018

Sci Rep

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In vertebrate retinal progenitor cells, the proneural factor Atoh7 exhibits a dynamic tissue and cellular expression pattern. Although the resulting Atoh7 retinal lineage contains all seven major cell types, only retinal ganglion cells require Atoh7 for proper differentiation. Such specificity necessitates complex regulation of Atoh7 transcription during retina development. The Notch signaling pathway is an evolutionarily conserved suppressor of proneural bHLH factor expression. Previous in vivo mouse genetic studies established the cell autonomous suppression of Atoh7 transcription by Notch1, Rbpj and Hes1. Here we identify four CSL binding sites within the Atoh7 proximal regulatory region and demonstrate Rbpj protein interaction at these sequences by in vitro electromobility shift, calorimetry and luciferase assays and, in vivo via colocalization and chromatin immunoprecipitation. We found that Rbpj simultaneously represses Atoh7 transcription using both Notch-dependent and –independent pathways.

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Section: Resultsmentioning

confidence: 99%

Rbpj direct regulation of Atoh7 transcription in the embryonic mouse retina

Miesfeld

Moon

Riesenberg

et al. 2018

Sci Rep

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“…Extracellular S2 cleavage is due to the tumor necrosis factor-alpha converting enzyme (TACE), whereas S3 intramembrane cleavage is operated by a gamma secretase, which catalyzes the release of the intracellular domain of Notch (N-ICD) into the cytoplasm. N-ICD then translocates inside the nucleus and forms a complex with RBPjk/CSL (CBF1/Su(H)/Lag-1) [ 13 ]. RBPjk is a DNA-binding transcription factor, which acts in a large complex with other proteins.…”

Section: Diversity Of Notch Signaling Mechanismsmentioning

confidence: 99%

Taming the Notch Transcriptional Regulator for Cancer Therapy

2018

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Notch signaling is a highly conserved pathway in all metazoans, which is deeply involved in the regulation of cell fate and differentiation, proliferation and migration during development. Research in the last decades has shown that the various components of the Notch signaling cascade are either upregulated or activated in human cancers. Therefore, its downregulation stands as a promising and powerful strategy for cancer therapy. Here, we discuss the recent advances in the development of small molecule inhibitors, blocking antibodies and oligonucleotides that hinder Notch activity, and their outcome in clinical trials. Although Notch was initially identified as an oncogene, later studies showed that it can also act as a tumor suppressor in certain contexts. Further complexity is added by the existence of numerous Notch family members, which exert different activities and can be differentially targeted by inhibitors, potentially accounting for contradictory data on their therapeutic efficacy. Notably, recent evidence supports the rationale for combinatorial treatments including Notch inhibitors, which appear to be more effective than single agents in fighting cancer.

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“…Notch signaling plays an important role in the tumor biology, including cell differentiation, proliferation, apoptosis, migration and invasion [ 7 – 10 ]. Increasing reports demonstrated that deregulation of Notch1 signaling can be observed in diverse tumor types, such as cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

Notch1 regulates the JNK signaling pathway and increases apoptosis in hepatocellular carcinoma

et al. 2017

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Notch1-induced pathways are involved in cell growth, apoptosis, motility, and invasion in many cancers. In the present study, the expression of Notch1 and NICD1 was detected in hepatocellular carcinoma (HCC) tissues using in-vitro assays. And then, we explored cell biology and signaling pathways using Notch1 siRNA or plasmids. Here, the expression of Notch1 and NICD1 was significantly decreased in HCC tissues. In-vitro, Notch1 plasmids inhibited cell proliferation, migration and invasion, but enhanced apoptosis of HepG2 and Hep3B cells. Conversely, si-Notch1 enhanced cell proliferation, migration and invasion, but inhibited apoptosis of HepG2 and Hep3B cells. Mechanically, Notch1 decreased the expression of cyclin D1, MMP-9 and Bcl-2, but increased the expression of p-JNK, Bax and cleaved caspase 3 in HepG2 and Hep3B cells. Besides, si-JNK or JNK inhibitor SP600125 affected the activation of Notch1 signaling pathway, and prevents cell apoptosis. In conclusion, Notch1 regulates the JNK signaling pathway and increases apoptosis in HCC. Because patients with HCC have a poor prognosis, Notch1 pathway may provide a novel treatment strategy.

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The CSL proteins, versatile transcription factors and context dependent corepressors of the notch signaling pathway

Cited by 32 publications

References 99 publications

Rbpj direct regulation of Atoh7 transcription in the embryonic mouse retina

Rbpj direct regulation of Atoh7 transcription in the embryonic mouse retina

Taming the Notch Transcriptional Regulator for Cancer Therapy

Notch1 regulates the JNK signaling pathway and increases apoptosis in hepatocellular carcinoma

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