Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways

Kikuchi, Ippei; Takahashi-Kanemitsu, Atsushi; Sakiyama, Natsuki; Tang, Chao; Tang, Pei Jung; Noda, Saori; Nakao, Kazuki; Kassai, Hidetoshi; Sato, Toshiro; Aiba, Atsu; Hatakeyama, Masanori

doi:10.1038/ncomms12887

Cited by 49 publications

(50 citation statements)

References 55 publications

(92 reference statements)

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“…We identified another tumor with a mutation in CDC73 , which encodes the RNA polymerase II–associated factor complex protein parafibromin and was recently reported to potentiate Notch signaling by binding to the NICD. 36 We also found an EP300 mutation in the validation cohort that could abrogate signaling of the Notch transcriptional complex. Of note, Notch signaling was reported to have a tumor suppressor function in GIST by down-regulating KIT mRNA expression.…”

Section: Discussionmentioning

confidence: 62%

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations

Burgoyne

Siena

Alkhuziem

et al. 2017

JCO Precision Oncology

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Purpose GI stromal tumors (GISTs) are commonly associated with somatic mutations in KIT and PDGFRA. However, a subset arises from mutations in NF1, most commonly associated with neurofibromatosis type 1. We define the anatomic distribution of NF1 alterations in GIST. Methods We describe the demographic/clinicopathologic features of 177 patients from two institutions whose GISTs underwent next-generation sequencing of ≥315 cancer-related genes. Results We initially identified six (9.7%) of 62 GISTs with NF1 genomic alterations from the first cohort. Of these six patients, five (83.3%) had unifocal tumors at the duodenal-jejunal flexure (DJF). Two additional patients with DJF GISTs had non-NF1 (KIT and BRAF) genomic alterations. After excluding one DJF GIST with an NF1 single nucleotide polymorphism, four (57.1%) of seven sequenced DJF tumors demonstrated deleterious NF1 alterations, whereas only one (1.8%) of 55 sequenced non-DJF GISTs had a deleterious NF1 somatic mutation (P < .001). One patient with DJF GIST had a germline NF1 variant that was associated with incomplete penetrance of clinical neurofibromatosis type 1 features along with a somatic NF1 mutation. Of the five DJF GISTs with any NF1 alteration, three (60%) had KIT mutations, and three (60%) had Notch pathway mutations (NOTCH2, MAML2, CDC73). We validated these findings in a second cohort of 115 GISTs, where two (40%) of five unifocal NF1-mutated GISTs arose at the DJF, and one of these also had a Notch pathway mutation (EP300). Conclusion Broad genomic profiling of adult GISTs has revealed that NF1 alterations are enriched in DJF GISTs. These tumors also may harbor concurrent activating KIT and/or inactivating Notch pathway mutations. In some cases, germline NF1 genetic testing may be appropriate for patients with DJF GISTs.

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Section: Discussionmentioning

confidence: 62%

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations

Burgoyne

Siena

Alkhuziem

et al. 2017

JCO Precision Oncology

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“…Further, HMGA1 expression has been found to be induced by transforming growth factor beta (TGF‐β) signalling through specificity protein 1 and phosphatidyl inositol‐3 kinase, resulting in enhanced tumourigenic properties in breast carcinoma . High Mobility Group AT‐hook 1 could arguably act downstream of the sonic hedgehog pathway to inactivate the tumour suppressor parafibromin (mutated hyperthyroidism jaw‐tumour 2) resulting in aberrant cell‐cycle progress . In breast carcinoma, HMGA1 is crucial to activation of several signalling pathways like Wnt, Notch, and Pin1‐dependent; TGF‐β/specificity protein 1/phosphatidyl inositol‐3 kinase; and Ras/extracellular signal‐regulated kinase (ERK) signalling pathways, which consequently boosts EMT.…”

Section: Discussionmentioning

confidence: 99%

miR‐214 activates TP53 but suppresses the expression of RELA, CTNNB1, and STAT3 in human cervical and colorectal cancer cells

Chandrasekaran

Sathyanarayanan

Karunagaran

2017

Cell Biochemistry & Function

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High Mobility Group AT-hook 1 (HMGA1) was identified as a target of miR-214 in human cervical and colorectal cancers (CaCx and CRC) in a previous study. While the expression of miR-214 remains suppressed, HMGA1 behaves as a potent oncogene and plays crucial roles in several aberrant signalling pathways by interacting with intermediates like RELA, CTNNB1, STAT3, and TP53 in CaCx and CRC. Hypothetically, miR-214 should be able to regulate the stabilization of some of these intermediates through the regulation of HMGA1. This was assessed by ectopically expressing miR-214 or complementarily, by inhibiting the expression of HMGA1. In promoter luciferase assays, miR-214 inhibited NF-κB and Wnt activities but elevated TP53 activity in cancer cells. Further, miR-214 suppressed the expression of HMGA1, RELA, CTNNB1, and STAT3 while elevating TP53 levels, similar to when small interfering RNA (siRNA) against HMGA1 was used, as revealed by Western blotting. It is suggested that poor expression of miR-214, commonly reported in CaCx and CRC tissues, may not only result in the sustained expression of HMGA1 but also that of RELA, CTNNB1, and STAT3, and a congruent suppression of TP53 during cancer initiation/progression. These several states are, however, reversed when miR-214 is reintroduced and could explain the tumour suppressive functions observed in earlier studies. Further studies are, however, required to reveal how microRNA-mediated regulation of HMGA1 expression may affect individual signalling pathways in CaCx and CRC. Current results reveal that miR-214 is not only able to regulate the expression of its direct target, HMGA1, but also that of a few signalling intermediates like TP53, RELA, CTNNB1, and STAT3, with which HMGA1 interacts. These intermediates play crucial roles in signalling pathways commonly deregulated in human CaCx and CRC. Hence, it is proposed that miR-214 might act as a tumour suppressor by regulating several aberrant signalling pathways through HMGA1. This knowledge has the potential to help design novel therapeutic strategies in CaCx and CRC.

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“…Several studies have also identified an important role for parafibromin, the human ortholog of Cdc73, in regulating the transcriptional output of the developmentally critical Wnt, Hedgehog, and Notch signaling pathways through direct interactions with the downstream effectors of these pathways [33, 50]. The interactions between parafibromin and the effectors of the Wnt and Hedgehog pathways (β-catenin and Gli1, respectively) utilize the same N-terminal segment of parafibromin and are mutually exclusive [50].…”

Section: Mechanisms Of Targeting Paf1c To Chromatinmentioning

confidence: 99%

“…The interactions between parafibromin and the effectors of the Wnt and Hedgehog pathways (β-catenin and Gli1, respectively) utilize the same N-terminal segment of parafibromin and are mutually exclusive [50]. In contrast, parafibromin can simultaneously interact with the Wnt and Notch signaling effectors, allowing for coordinate stimulation of these two pathways.…”

Section: Mechanisms Of Targeting Paf1c To Chromatinmentioning

confidence: 99%

Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation

Oss

Cucinotta

Arndt

2017

Trends in Biochemical Sciences

143

132

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The conserved, multifunctional Paf1 complex (Paf1C) regulates all stages of the RNA polymerase II transcription cycle. In this review, we examine a diverse set of recent studies from various organisms that build on foundational studies in budding yeast. These studies identify new roles for Paf1C in the control of gene expression and the regulation of chromatin structure. In exploring these advances, we find that Paf1C’s various functions, such as the regulation of promoter-proximal pausing and development in higher eukaryotes, are complex and context-dependent. As more becomes known about the role of Paf1C in human disease, interest in the molecular mechanisms underpinning Paf1C function will continue to increase.

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Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways

Cited by 49 publications

References 55 publications

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations

miR‐214 activates TP53 but suppresses the expression of RELA, CTNNB1, and STAT3 in human cervical and colorectal cancer cells

Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation

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