Extension of the Notch intracellular domain ankyrin repeat stack by NRARP promotes feedback inhibition of Notch signaling

Jarrett, Sanchez M.; Seegar, T.C.M.; Andrews, Mark; Adelmant, Guillaume; Marto, Jarrod A.; Aster, Jon C.; Blacklow, Stephen C.

doi:10.1126/scisignal.aay2369

Cited by 23 publications

(12 citation statements)

References 44 publications

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“…HEY1 is regulated by MAML1 in melanoma [ 54 ] and human umbilical venous endothelial cells [ 55 ]. NRARP is a negative regulator of Notch signaling [ 56 ] and in Xenopus, the NRARP complex can include Mastermind [ 57 ]. SPP1 is a direct target of the Notch pathway in osteoblasts [ 51 ] and human hepatocellular carcinoma [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

MAML1: a coregulator that alters endometrial epithelial cell adhesive capacity

Zafir

Zhou

Menkhorst

et al. 2021

Fertil Res and Pract

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Background Abnormalities in endometrial receptivity has been identified as a major barrier to successful embryo implantation. Endometrial receptivity refers to the conformational and biochemical changes occurring in the endometrial epithelial layer which make it adhesive and receptive to blastocyst attachment. This takes place during the mid-secretory phase of woman’s menstrual cycle and is a result of a delicate interplay between numerous hormones, cytokines and other factors. Outside of this window, the endometrium is refractory to an implanting blastocyst. It has been shown that Notch ligands and receptors are dysregulated in the endometrium of infertile women. Mastermind Like Transcriptional Coactivator 1 (MAML1) is a known coactivator of the Notch signaling pathway. This study aimed to determine the role of MAML1 in regulating endometrial receptivity. Methods The expression and localization of MAML1 in the fertile human endometrium (non-receptive proliferative phase versus receptive mid-secretory phase) were determined by immunohistochemistry. Ishikawa cells were used as an endometrial epithelial model to investigate the functional consequences of MAML1 knockdown on endometrial adhesive capacity to HTR8/SVneo (trophoblast cell line) spheroids. After MAML1 knockdown in Ishikawa cells, the expression of endometrial receptivity markers and Notch dependent and independent pathway members were assessed by qPCR. Two-tailed unpaired or paired student’s t-test were used for statistical analysis with a significance threshold of P < 0.05. Results MAML1 was localized in the luminal epithelium, glandular epithelium and stroma of human endometrium and the increased expression identified in the mid-secretory phase was restricted only to the luminal epithelium (P < 0.05). Functional analysis using Ishikawa cells demonstrated that knockdown of MAML1 significantly reduced epithelial adhesive capacity (P < 0.01) to HTR8/SVneo (trophoblast cell line) spheroids compared to control. MAML1 knockdown significantly affected the expression of classical receptivity markers (SPP1, DPP4) and this response was not directly via hormone receptors. The expression level of Hippo pathway target Ankyrin repeat domain-containing protein 1 (ANKRD1) was also affected after MAML1 knockdown in Ishikawa cells. Conclusion Our data strongly suggest that MAML1 is involved in regulating the endometrial adhesive capacity and may facilitate embryo attachment, either directly or indirectly through the Notch signaling pathway.

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Section: Discussionmentioning

confidence: 99%

MAML1: a coregulator that alters endometrial epithelial cell adhesive capacity

Zafir

Zhou

Menkhorst

et al. 2021

Fertil Res and Pract

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“…This confirmed the Notch responsiveness of all genes tested, and also revealed variation in the kinetics of response, even among "canonical" Notch target genes. For example, HES1 showed fast induction followed by rapid down-regulation, consistent with autoinhibition (Hirata et al, 2002), whereas HES4, HES5, and NRARP (a feedback inhibitor of NTC function (Jarrett et al, 2019)) showed more sustained increases in expression ( Figure 2C).…”

Section: Identification Of a Notch-induced Program Of Gene Expressionmentioning

confidence: 75%

IER5, a DNA-damage response gene, is required for Notch-mediated induction of squamous cell differentiation

Lemieux

Thomas

et al. 2020

Preprint

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Notch signaling regulates normal squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is a key tumor suppressive pathway. To identify the direct targets of Notch that produce these phenotypes, we introduced a conditional Notch transgene into squamous cell carcinoma cell lines, which respond to Notch activation in 2D culture and in organoid cultures by undergoing differentiation. RNA-seq and ChIP-seq analyses show that in squamous cells Notch activates a context-specific program of gene expression that depends on lineage-specific regulatory elements, most of which lie in longrange enhancers. Among the direct Notch target genes are multiple DNA damage response genes, including IER5, which is regulated by Notch through several enhancer elements. We show that IER5 is required for Notch-induced differentiation in squamous carcinoma cells and in TERT-immortalized keratinocytes. Its function is epistatic to PPP2R2A, which encodes the B55a subunit of PP2A, and IER5 interacts with B55a in cells and in purified systems. These results show that Notch and DNA-damage response pathways converge in squamous cells and that some components of these pathways promote differentiation, which may serve to eliminate DNA-damaged cells from the proliferative pool in squamous epithelia. Crosstalk involving Notch and PP2A may enable Notch signaling to be tuned and integrated with other pathways that regulate squamous differentiation. Our work also suggests that squamous cell carcinomas remain responsive to Notch signaling, providing a rationale for reactivation of Notch as a therapeutic strategy in these cancers. ImpactOur findings highlight context-specific crosstalk between Notch, DNA damage response genes, and PP2A, and provide a roadmap for understanding how Notch induces the differentiation of squamous cells.

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“…HIPK2 overexpression was reported in papillomavirus-positive tonsillar squamous cell carcinoma and correlated with the prognosis of patients [22]. HIPK2 regulates malignant growth through the phosphorylation of Notch1 [23]. Many studies also revealed the anti-tumorigenic mechanisms of HIPK2, such as apoptosis stimulation, angiogenesis inhibition, and metastasis prevention [17].…”

Section: Discussionmentioning

confidence: 99%

HIPK2 reduces the resistance of gastric cancer cells to cisplatin via p53 pathway

Mi¹,

Zhang²,

Jia³

2021

Trop. J. Pharm Res

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Purpose: To uncover the functional effect of homologous domain-associated protein kinase 2 (HIPK2) on the viability of cisplatin (DDP)-resistant gastric cancer (GC) cells and elucidate the possible mechanism of action.Methods: The effect of DDP on GC viability and apoptotic rate was evaluated using MTT and flow cytometry (FCM) assays. The potential effect of HIPK2 on DDP sensitivity and cell apoptosis was investigated in the presence of cisplatin while the effect of HIPK2 on p53 activation was determined by immunoblot assay.Results: HIPK2 expression was decreased in DDP-resistant GC cell while upregulation of HIPK2 reduced growth, but promoted apoptosis in DDP-resistant GC cells. Further investigations showed that HIPK2 promoted p53 activation, while suppression of p53 weakened the inhibitory effect of HIPK2 on DDP-resistance in GC cells.Conclusion: The results suggest that HIPK2 is a promising and important therapeutic factor for the regulation of the resistance of GC cells to DDP. Thus, may have a role to play in the management of gastric cancer Keywords: Gastric cancer, Cisplatin, HIPK2, Homologous domain-associated protein kinase 2, p53 pathway, Therapeutic target

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Extension of the Notch intracellular domain ankyrin repeat stack by NRARP promotes feedback inhibition of Notch signaling

Cited by 23 publications

References 44 publications

MAML1: a coregulator that alters endometrial epithelial cell adhesive capacity

MAML1: a coregulator that alters endometrial epithelial cell adhesive capacity

IER5, a DNA-damage response gene, is required for Notch-mediated induction of squamous cell differentiation

HIPK2 reduces the resistance of gastric cancer cells to cisplatin via p53 pathway

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