Functional Consequences of Differential O-glycosylation of MUC1, MUC4, and MUC16 (Downstream Effects on Signaling)

Hanson, Ryan L.; Hollingsworth, Michael A.

doi:10.3390/biom6030034

Cited by 64 publications

(50 citation statements)

References 153 publications

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“…Therefore, using EXoO allowed detailed mapping of over one hundred sites on VCAN and MUC1. MUC1 has been reported to be an important molecule in many research areas including different cancers, immunity, and immunotherapy (Hanisch, ; Tarp & Clausen, ; Beatson et al , ; Hanson & Hollingsworth, ). The use of EXoO therefore is advantageous to reveal new biological insight regarding mucin‐type glycoproteins.…”

Section: Discussionmentioning

confidence: 99%

Mapping the O‐glycoproteome using site‐specific extraction of O‐linked glycopeptides (EXoO)

Yang

et al. 2018

Molecular Systems Biology

128

181

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Protein glycosylation is one of the most abundant post‐translational modifications. However, detailed analysis of O‐linked glycosylation, a major type of protein glycosylation, has been severely impeded by the scarcity of suitable methodologies. Here, a chemoenzymatic method is introduced for the site‐specific extraction of O‐linked glycopeptides (EXoO), which enabled the mapping of over 3,000 O‐linked glycosylation sites and definition of their glycans on over 1,000 proteins in human kidney tissues, T cells, and serum. This large‐scale localization of O‐linked glycosylation sites demonstrated that EXoO is an effective method for defining the site‐specific O‐linked glycoproteome in different types of sample. Detailed structural analysis of the sites identified revealed conserved motifs and topological orientations facing extracellular space, the cell surface, the lumen of the Golgi, and the endoplasmic reticulum (ER). EXoO was also able to reveal significant differences in the O‐linked glycoproteome of tumor and normal kidney tissues pointing to its broader use in clinical diagnostics and therapeutics.

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Section: Discussionmentioning

confidence: 99%

Mapping the O‐glycoproteome using site‐specific extraction of O‐linked glycopeptides (EXoO)

Yang

et al. 2018

Molecular Systems Biology

128

181

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“…Moreover, downregulation of NCOR1 in dendritic cells has been reported to induce FoxP3 + regulatory T cells by inhibiting Th17 cell development [35]. In addition, aberrant glycosylation of mucins interferes with the ability of natural killer cells to destroy tumor cells, suggesting immunosuppression around the tumor [32]. However, the association between mutations in such genes and CDK4/6 inhibitor resistance observed herein has never been documented thus far.…”

Section: Discussionmentioning

confidence: 78%

“…In particular, surface mucin genes, which play important roles in protecting epithelial cells and have been implicated in epithelial renewal and differentiation [30], were highly mutated in T47D-PR cells (Table 2). These mucin genes were also reported to be involved in immune regulation [31,32]. Visualization of GO revealing prominent immune process involvement in palbociclib-resistant cells GO enriched terms in the 107 genes with mutations in T47D or T47D-PR cells ( Supplementary Fig.…”

Section: Mutation Pro Ling Revealing Deregulation Of Immune Pathway Imentioning

confidence: 94%

Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative Genomics and Transcriptomics

Pandey

Lee

Park

et al. 2020

Preprint

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Background: Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been widely used to treat advanced hormone receptor-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Hence, understanding the mechanisms of acquired resistance to CDK4/6 inhibitors is crucial for developing alternative treatment strategies. Therefore, the present study screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Methods: Palbociclib-resistant cells, MCF7-PR and T47D-PR, were generated by exposing MCF7 and T47D cells to palbociclib. After confirming acquired resistance through in vitro assays, whole-exome sequencing (WES) and mRNA microarray were performed to compare the genomic and transcriptomic landscape between palbociclib-sensitive and resistant cells. Real time-PCR was performed to confirm differentially expressed genes.Results: Microarray analysis comparing MCF7 and MCF7-PR cells revealed 651 differentially expressed genes (DEGs) (fold change >2 or <0.5), while WES comparing T47D and T47D-PR cells revealed 107 mutated genes. Furthermore, pathway analysis of both DEGs and mutated genes revealed immune pathway deregulation commonly observed in MCF7-PR and T47D-PR cells. Notably, DEG annotation revealed activation of type I interferon pathway, activation of immune checkpoint inhibitory pathway, and suppression of immune checkpoint stimulatory pathway in palbociclib-resistant cells. Moreover, mutations in NCOR1, MUC4 and MUC16 genes found in palbociclib-resistant cells were annotated to be related to the immune pathway. Conclusions: Palbociclib resistance was found to be associated with deregulated immune pathway in preclinical breast cancer models. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance.

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“…Numerous biologically interesting examples of rapid protein repeat evolution were characterized via manual analyses, e.g. in protein families associated with neural development, host-pathogen interactions (Schüler and Bornberg-Bauer 2016) , speciation events (Schwartz et al 2014;Tromer et al 2015) , human disease (Hanson and Hollingsworth 2016;Yeon et al 2017) and repression of transposons (Jacobs et al 2014;Yang et al 2017) . For example, recombination regulator PRDM9 has a rapidly evolving zinc finger array (Schaper et al 2014;Schüler and Bornberg-Bauer 2016) and has been implicated in (hybrid) sterility and speciation (Schwartz et al 2014) .…”

Section: Introductionmentioning

confidence: 99%

PhyRepID: a comparative phylogenomics approach for large-scale quantification of protein repeat evolution

Belzen

Deutekom

Snel

2020

Preprint

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Protein repeats consisting of domains or motifs are involved in key biological processes such as neural development, host-pathogen interactions, and speciation. Expansion and contraction of these repeats can strongly impact protein function as was shown for KNL1 and PRDM9.However, these known cases could only be identified manually and were previously incorrectly reported as conserved in large-scale analyses, because signatures of repeat evolution are difficult to resolve automatically.We developed PhyRepID to compare protein domain repeat evolution and analysed 4939 groups of orthologous proteins (OGs) from 14 vertebrate species. Our main contributions are 1) detecting a wide scope of repeats consisting of Pfam structural domains and motifs, 2) improving sensitivity and precision of repeat unit detection through optimization for the OGs, 3) using phylogenetic analysis to detect evolution within repeat regions. From these phylogenetic signals, we derived a "protein repeat duplication" (PRD) score that quantifies evolution in repeat regions and thereby enables large-scale comparison of protein families. Zinc finger repeats show remarkably fast evolution, comprising 25 of 100 fastest evolving proteins in our dataset, whilst cooperatively-folding domain repeats like beta-propellers are mostly conserved. Motif repeats have a similar PRD score distribution as domain repeats and also show a large diversity in evolutionary rates. A ranking based on the PRD score reflects previous manual observations of both highly conserved (CDC20) and rapidly evolving repeats (KNL1, PRDM9) and proposes novel candidates (e.g. AHNAK, PRX, SPATA31) showing previously undescribed rapid repeat evolution. PhyRepID is available on https://github.com/ivanbelzen/PhyRepID/ .

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Functional Consequences of Differential O-glycosylation of MUC1, MUC4, and MUC16 (Downstream Effects on Signaling)

Cited by 64 publications

References 153 publications

Mapping the O‐glycoproteome using site‐specific extraction of O‐linked glycopeptides (EXoO)

Mapping the O‐glycoproteome using site‐specific extraction of O‐linked glycopeptides (EXoO)

Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative Genomics and Transcriptomics

PhyRepID: a comparative phylogenomics approach for large-scale quantification of protein repeat evolution

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