Chemical Genetics Reveals a Role of dCTP Pyrophosphatase 1 in Wnt Signaling

Friese, Alexandra; Kapoor, Shobhna; Schneidewind, Tabea; Vidadala, Srinivasa Rao; Sardana, Juhi; Brause, Alexandra; Förster, Tim; Bischoff, Matthias; Wagner, Jessica; Janning, Petra; Ziegler, Slava; Waldmann, Herbert

doi:10.1002/anie.201905977

Cited by 15 publications

(13 citation statements)

References 19 publications

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“…5E and 5F ) obtained from Osterix-Cre(+); Kcnma1f/f mice compared with Osterix-Cre(–); Kcnma1f/f mice. Additionally, the expression of USP7, which seems to have a direct interaction with the Wnt/β-catenin pathway ( Friese et al, 2019 ), was increased in the bones and osteoblasts of Osterix-Cre(+); Kcnma1f/f mice.…”

Section: Resultsmentioning

confidence: 99%

BK Channel Deficiency in Osteoblasts Reduces Bone Formation via the Wnt/β-Catenin Pathway

Jiang

Yang

Gao

et al. 2021

Molecules and Cells

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Global knockout of the BK channel has been proven to affect bone formation; however, whether it directly affects osteoblast differentiation and the mechanism are elusive. In the current study, we further investigated the role of BK channels in bone development and explored whether BK channels impacted the differentiation and proliferation of osteoblasts via the canonical Wnt signaling pathway. Our findings demonstrated that knockout of Kcnma1 disrupted the osteogenesis of osteoblasts and inhibited the stabilization of β-catenin. Western blot analysis showed that the protein levels of Axin1 and USP7 increased when Kcnma1 was deficient. Together, this study confirmed that BK ablation decreased bone mass via the Wnt/β-catenin signaling pathway. Our findings also showed that USP7 might have the ability to stabilize the activity of Axin1, which would increase the degradation of β-catenin in osteoblasts.

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Section: Resultsmentioning

confidence: 99%

BK Channel Deficiency in Osteoblasts Reduces Bone Formation via the Wnt/β-Catenin Pathway

Jiang

Yang

Gao

et al. 2021

Molecules and Cells

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“…MazG in Mycobacterium tuberculosis hydrolyzes dUTP, 2-hydroxy-dATP and 8-oxo-dGTP. The deletion of this enzyme can cause a significant increase in the mutation of the gene encoding rifampicin resistance, thereby affecting the normal growth of Mycobacterium tuberculosis [14]. Therefore, NTP-PPase continuously breaks down the abnormal nucleotides in the cell metabolism process in the biological process, ensuring the accuracy of DNA replication and the stability of the organism's genome.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the Expression and Prognosis for DCTPP1 gene in Breast Cancer

Hoang

Bui

Nguyễn³

2021

Asian Pac J Cancer Biol

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Background: Breast cancer is a common malignancy in women. DCTPP1 is a potential target for the development of antitumor drugs, and plays an important role in the process of DNA replication. Aims: To investigate the biological role of DCTPP1 gene, as well as its expression in breast cancer and its relation to patient prognosis. Materials and Methods: Breast cancer data was derived from the TCGA database. Using the UALCAN database, the expression level of DCTPP1 mRNA in breast cancer tissues was investigated. The expression of DCTPP1 in various pathological types of breast cancer was studied using the Human Protein Atlas. UALCAN was also used to investigate the relationship between DCTPP1 gene expression and breast cancer patient prognosis. Bioinformatics studied the proteins related to DCTPP1 expression and their roles in the GeneMANIA and WebGestalt databases. Results: DCTPP1 mRNA was significantly expressed in breast cancer compared to normal breast tissue (P<0.001). DCTPP1 was shown to be highly expressed in breast cancer tissues from different pathological types and stages (P<0.001). The DCTPP1 protein was expressed at a higher frequency in breast cancer than in normal breast tissue. When compared to patients with low DCTPP1 expression, patients with high DCTPP1 expression had a considerably shorter overall survival time. The 20 proteins related to DCTPP1 expression were mostly located in the nucleus and membrane, and were involved in biological regulation, stimulus response, metabolic process, and other processes, according to gene ontology analysis. It plays an important role in protein binding, ion binding, and nucleic acid binding. Conclusion: DCTPP1 is highly expressed in breast cancer, and is associated to a poor prognosis for patients with breast cancer. DCTPP1 may be a potential therapy and intervention target for breast cancer.

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“…As a housekeeping nucleotide hydrolase, dCT pyrophosphatase 1 (dCTPP1) decreases the intracellular level of deoxycutidine triphosphate (dCTP) and its subsequent insertion into nascent DNA during replication by catalyzing the hydrolysis of dNTPs to their corresponding monophosphates. It was not considered to be an important regulator of WNT signaling until Friese et al identified the WNT signaling inhibitor pyrcoumin ( 117 ) (Figure ), which displayed an IC 50 value of 8.4 μM in the STF reporter assay . Target validation by affinity-based chemical proteomics using probe 118 revealed that dCTPP1 is the target of 117 .…”

Section: Emerging Targets and Small-molecule Inhibitors In The Canoni...mentioning

confidence: 99%

“…It was not considered to be an important regulator of WNT signaling until Friese et al identified the WNT signaling inhibitor pyrcoumin (117) (Figure 29), which displayed an IC 50 value of 8.4 μM in the STF reporter assay. 182 Target validation by affinity-based chemical proteomics using probe 118 revealed that dCTPP1 is the target of 117. A pull-down experiment using immunoblotting and a cellular thermal shift assay further confirmed this interaction.…”

Section: Emerging Targets and Small-moleculementioning

confidence: 99%

Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer

et al. 2021

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Canonical WNT signaling is an important developmental pathway that has attracted increased attention for anticancer drug discovery. From the production and secretion of WNT ligands, their binding to membrane receptors, and the β-catenin destruction complex to the expansive β-catenin transcriptional complex, multiple components have been investigated as drug targets to modulate WNT signaling. Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, β-catenin/coactivators, protein–protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (e.g., LGK-974, PRI-724, and ETC-159) in human clinical trials. Herein we summarize recent progress in the drug discovery and development of small-molecule inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochemical properties, and therapeutic potential. The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted.

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Chemical Genetics Reveals a Role of dCTP Pyrophosphatase 1 in Wnt Signaling

Cited by 15 publications

References 19 publications

BK Channel Deficiency in Osteoblasts Reduces Bone Formation via the Wnt/β-Catenin Pathway

BK Channel Deficiency in Osteoblasts Reduces Bone Formation via the Wnt/β-Catenin Pathway

Comprehensive Analysis of the Expression and Prognosis for DCTPP1 gene in Breast Cancer

Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer

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