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5. MUC13 negatively regulates tight junction proteins and intestinal epithelial barrier integrity via Protein Kinase C

Author

Infectiebiologie, Afd Biomol.Mass Spect. and Proteomics, Pathobiologie, Celbiologie, IOV CCB, Infectious Diseases and Immunology - Infection Biology, Cell Biology, Metabolism & Cancer - Cancer, Cell Biology, Metabolism & Cancer - Cellbiology, Segui-Perez, Celia, Stapels, Daphne A C, Ma, Ziliang, Su, Jinyi, Passchier, Elsemieke, Westendorp, Bart, Wubbolts, Richard W, Wu, Wei, van Putten, Jos P M, Strijbis, Karin, Infectiebiologie, Afd Biomol.Mass Spect. and Proteomics, Pathobiologie, Celbiologie, IOV CCB, Infectious Diseases and Immunology - Infection Biology, Cell Biology, Metabolism & Cancer - Cancer, Cell Biology, Metabolism & Cancer - Cellbiology, Segui-Perez, Celia, Stapels, Daphne A C, Ma, Ziliang, Su, Jinyi, Passchier, Elsemieke, Westendorp, Bart, Wubbolts, Richard W, Wu, Wei, van Putten, Jos P M, and Strijbis, Karin

Published
2024

6. A reverse brake for the cell cycle

Author

Pathobiologie, Cell Biology, Metabolism & Cancer - Cancer, Westendorp, Bart, Pathobiologie, Cell Biology, Metabolism & Cancer - Cancer, and Westendorp, Bart

Published
2024

7. Assessment of Kinome-wide Activity Remodeling Upon Picornavirus Infection

Author

Afd Biomol.Mass Spect. and Proteomics, Virologie, Pathobiologie, Faculteit Diergeneeskunde, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Infectious Diseases and Immunology - Virology, Cell Biology, Metabolism & Cancer - Cancer, Cell Biology, Metabolism & Cancer - Metabolomics, Veth, Tim S, Nouwen, Lonneke V, Zwaagstra, Marleen, Lyoo, Heyrhyoung, Wierenga, Kathryn A, Westendorp, Bart, Altelaar, Maarten A F M, Berkers, Celia, van Kuppeveld, Frank J M, Heck, Albert J R, Afd Biomol.Mass Spect. and Proteomics, Virologie, Pathobiologie, Faculteit Diergeneeskunde, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Infectious Diseases and Immunology - Virology, Cell Biology, Metabolism & Cancer - Cancer, Cell Biology, Metabolism & Cancer - Metabolomics, Veth, Tim S, Nouwen, Lonneke V, Zwaagstra, Marleen, Lyoo, Heyrhyoung, Wierenga, Kathryn A, Westendorp, Bart, Altelaar, Maarten A F M, Berkers, Celia, van Kuppeveld, Frank J M, and Heck, Albert J R

Published
2024

8. Stochastic variation in the FOXM1 transcription program mediates replication stress tolerance

Author

Pathobiologie, Chirurgie, CS_Locomotion, Cell Biology, Metabolism & Cancer - Cancer, Locomotion - Surgery (CA), Segeren, Hendrika A., Wierenga, Kathryn A., Riemers, Frank M., Liere, Elsbeth A. van, Westendorp, Bart, Pathobiologie, Chirurgie, CS_Locomotion, Cell Biology, Metabolism & Cancer - Cancer, Locomotion - Surgery (CA), Segeren, Hendrika A., Wierenga, Kathryn A., Riemers, Frank M., Liere, Elsbeth A. van, and Westendorp, Bart

Published
2024

10. MUC13 negatively regulates tight junction proteins and intestinal epithelial barrier integrity via protein kinase C.

Author

Segui-Perez, Celia, Stapels, Daphne A. C., Ziliang Ma, Jinyi Su, Passchier, Elsemieke, Westendorp, Bart, Wubbolts, Richard W., Wei Wu, van Putten, Jos P. M., and Strijbis, Karin

Subjects
CLAUDINS, OCCLUDINS, TIGHT junctions, INTESTINAL barrier function, PROTEIN kinases, PROTEIN kinase C, INTESTINAL mucosa
Abstract

Glycosylated mucin proteins contribute to the essential barrier function of the intestinal epithelium. The transmembrane mucin MUC13 is an abundant intestinal glycoprotein with important functions for mucosal maintenance that are not yet completely understood. We demonstrate that in human intestinal epithelialmonolayers, MUC13 localized to both the apical surface and the tight junction (TJ) region on the lateral membrane. MUC13 deletion resulted in increased transepithelial resistance (TEER) and reduced translocation of small solutes. TEER buildup in ΔMUC13 cells could be prevented by addition of MLCK, ROCK or protein kinase C (PKC) inhibitors. The levels of TJ proteins including claudins and occludin were highly increased in membrane fractions of MUC13 knockout cells. Removal of the MUC13 cytoplasmic tail (CT) also altered TJ composition but did not affect TEER. The increased buildup of TJ complexes in ΔMUC13 and MUC13-ΔCT cells was dependent on PKC. The responsible PKC member might be PKCd (or PRKCD) based on elevated protein levels in the absence of full-length MUC13. Our results demonstrate for the first time that a mucin protein can negatively regulate TJ function and stimulate intestinal barrier permeability. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Glycosylated extracellular mucin domains protect against SARS-CoV-2 infection at the respiratory surface

Author

Chatterjee, Maitrayee, primary, Huang, Liane Z. X., additional, Mykytyn, Anna Z., additional, Wang, Chunyan, additional, Lamers, Mart M., additional, Westendorp, Bart, additional, Wubbolts, Richard W., additional, van Putten, Jos P. M., additional, Bosch, Berend-Jan, additional, Haagmans, Bart L., additional, and Strijbis, Karin, additional

Published
2023
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12. Inhibition of polyploidization in Pten-deficient livers reduces steatosis

Author

Moreno, Eva, Matondo, Augustine B, Bongiovanni, Laura, van de Lest, Chris H A, Molenaar, Martijn R, Toussaint, Mathilda J M, van Essen, Saskia C, Houweling, Martin, Helms, J Bernd, Westendorp, Bart, de Bruin, Alain, Cell Biology, Metabolism and Cancer, Pathobiologie, CS_Locomotion, Veterinaire biochemie, Equine Musculoskeletal Biology, Dep Biomolecular Health Sciences, Cell Biology, Metabolism and Cancer, Pathobiologie, CS_Locomotion, Veterinaire biochemie, Equine Musculoskeletal Biology, and Dep Biomolecular Health Sciences

Subjects
EXPRESSION, PTEN, GENES, Hepatology, Liver Neoplasms, Peroxisome Proliferator-Activated Receptors, PTEN Phosphohydrolase, non-alcoholic fatty liver disease, FATTY LIVER, hepatocellular carcinoma, polyploidization, Lipids, HEPATOCYTE PLOIDY, atypical E2Fs, Mice, Phosphatidylinositol 3-Kinases, FUSION, Liver, conditional knockout mice, Hepatocytes, steatosis, Animals, E2F8, Proto-Oncogene Proteins c-akt, SUPPRESSION
Abstract

The tumour suppressor PTEN is a negative regulator of the PI3K/AKT signalling pathway. Liver-specific deletion of Pten in mice results in the hyper-activation PI3K/AKT signalling accompanied by enhanced genome duplication (polyploidization), marked lipid accumulation (steatosis) and formation of hepatocellular carcinomas. However, it is unknown whether polyploidization in this model has an impact on the development of steatosis and the progression towards liver cancer. Here, we used a liver-specific conditional knockout approach to delete Pten in combination with deletion of E2f7/8, known key inducers of polyploidization. As expected, Pten deletion caused severe steatosis and liver tumours accompanied by enhanced polyploidization. Additional deletion of E2f7/8 inhibited polyploidization, alleviated Pten-induced steatosis without affecting lipid species composition and accelerated liver tumour progression. Global transcriptomic analysis showed that inhibition of polyploidization in Pten-deficient livers resulted in reduced expression of genes involved in energy metabolism, including PPAR-gamma signalling. However, we find no evidence that deregulated genes in Pten-deficient livers are direct transcriptional targets of E2F7/8, supporting that reduction in steatosis and progression towards liver cancer are likely consequences of inhibiting polyploidization. Lastly, flow cytometry and image analysis on isolated primary wildtype mouse hepatocytes provided further support that polyploid cells can accumulate more lipid droplets than diploid hepatocytes. Collectively, we show that polyploidization promotes steatosis and function as an important barrier against liver tumour progression in Pten-deficient livers.

Published
2022

15. Glycosylated extracellular mucin domains protect against SARS-CoV-2 infection at the respiratory surface

Author

Infectiebiologie, Virologie, Pathobiologie, Cell Biology, Metabolism & Cancer - Cancer, Infectious Diseases and Immunology - Infection Biology, Infectious Diseases and Immunology - Virology, Cell Biology, Metabolism & Cancer - Cellbiology, Chatterjee, Maitrayee, Huang, Liane Z X, Mykytyn, Anna Z, Wang, Chunyan, Lamers, Mart M, Westendorp, Bart, Wubbolts, Richard W, van Putten, Jos P M, Bosch, Berend-Jan, Haagmans, Bart L, Strijbis, Karin, Infectiebiologie, Virologie, Pathobiologie, Cell Biology, Metabolism & Cancer - Cancer, Infectious Diseases and Immunology - Infection Biology, Infectious Diseases and Immunology - Virology, Cell Biology, Metabolism & Cancer - Cellbiology, Chatterjee, Maitrayee, Huang, Liane Z X, Mykytyn, Anna Z, Wang, Chunyan, Lamers, Mart M, Westendorp, Bart, Wubbolts, Richard W, van Putten, Jos P M, Bosch, Berend-Jan, Haagmans, Bart L, and Strijbis, Karin

Published
2023

16. Glycosylated extracellular mucin domains protect against SARS-CoV-2 infection at the respiratory surface

Author

Chatterjee, Maitrayee, Huang, Liane Z.X., Mykytyn, Anna Z., Wang, Chunyan, Lamers, Mart M., Westendorp, Bart, Wubbolts, Richard W., van Putten, Jos P.M., Bosch, Berend Jan, Haagmans, Bart L., Strijbis, Karin, Chatterjee, Maitrayee, Huang, Liane Z.X., Mykytyn, Anna Z., Wang, Chunyan, Lamers, Mart M., Westendorp, Bart, Wubbolts, Richard W., van Putten, Jos P.M., Bosch, Berend Jan, Haagmans, Bart L., and Strijbis, Karin

Abstract

Mucins play an essential role in protecting the respiratory tract against microbial infections while also acting as binding sites for bacterial and viral adhesins. The heavily O-glycosylated gel-forming mucins MUC5AC and MUC5B eliminate pathogens by mucociliary clearance. Transmembrane mucins MUC1, MUC4, and MUC16 can restrict microbial invasion at the apical surface of the epithelium. In this study, we determined the impact of host mucins and mucin glycans on epithelial entry of SARS-CoV-2. Human lung epithelial Calu-3 cells express the SARS-CoV-2 entry receptor ACE2 and high levels of glycosylated MUC1, but not MUC4 and MUC16, on their cell surface. The O-glycan-specific mucinase StcE specifically removed the glycosylated part of the MUC1 extracellular domain while leaving the underlying SEA domain and cytoplasmic tail intact. StcE treatment of Calu-3 cells significantly enhanced infection with SARS-CoV-2 pseudovirus and authentic virus, while removal of sialic acid and fucose from the epithelial surface did not impact viral entry. In Calu-3 cells, the transmembrane mucin MUC1 and ACE2 are located to the apical surface in close proximity and StcE treatment results in enhanced binding of purified spike protein. Both MUC1 and MUC16 are expressed on the surface of human organoid-derived air-liquid interface (ALI) differentiated airway cultures and StcE treatment led to mucin removal and increased levels of SARS-CoV-2 replication. In these cultures, MUC1 was highly expressed in non-ciliated cells while MUC16 was enriched in goblet cells. In conclusion, the glycosylated extracellular domains of different transmembrane mucins might have similar protective functions in different respiratory cell types by restricting SARS-CoV-2 binding and entry.

Published
2023

19. Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma

Author

Kent, Lindsey N., Bae, Sooin, Tsai, Shih-Yin, Tang, Xing, Srivastava, Arunima, Koivisto, Christopher, Martin, Chelsea K., Ridolfi, Elisa, Miller, Grace C., Zorko, Sarah M., Plevris, Emilia, Hadjiyannis, Yannis, Perez, Miguel, Nolan, Eric, Kladney, Raleigh, Westendorp, Bart, de Bruin, Alain, Fernandez, Soledad, Rosol, Thomas J., Pohar, Kamal S., Pipas, James M., and Leone, Gustavo

Subjects
Hepatocellular carcinoma -- Genetic aspects -- Risk factors, Gene mutation -- Analysis -- Research, Transcription factors -- Research, DNA binding proteins -- Research, Health care industry
Abstract

Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer., Introduction The E2F family of transcription factors consists of 8 members that can be organized into 3 subcategories based on function and expression patterns during the cell cycle: activators (E2F1-3), [...]

Published
2017
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22. E2f8 mediates tumor suppression in postnatal liver development

Author

Kent, Lindsey N., Rakijas, Jessica B., Pandit, Shusil K., Westendorp, Bart, Chen, Hui-Zi, Huntington, Justin T., Tang, Xing, Bae, Sooin, Srivastava, Arunima, Senapati, Shantibhusan, Koivisto, Christopher, Martin, Chelsea K., Cuitino, Maria C., Perez, Miguel, Clouse, Julian M., Chokshi, Veda, Shinde, Neelam, Kladney, Raleigh, Sun, Daokun, Perez-Castro, Antonio, Matondo, Ramadhan B., Nantasanti, Sathidpak, Mokry, Michal, Huang, Kun, Machiraju, Raghu, Fernandez, Soledad, Rosol, Thomas J., Coppola, Vincenzo, Pohar, Kamal S., Pipas, James M., Schmidt, Carl R., de Bruin, Alain, and Leone, Gustavo

Subjects
Tumor suppressor genes -- Properties, Infants -- Development, Liver -- Genetic aspects, Health care industry
Abstract

E2F-mediated transcriptional repression of cell cycle-dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8's tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8's DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development., Introduction The E2F family members form a core transcriptional axis crucial for coordinating cell cycle transitions. Traditionally, E2Fs have been categorized into 3 groups based on their transcriptional activity, expression, [...]

Published
2016
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23. Excessive E2F Transcription in Single Cancer Cells Precludes Transient Cell-Cycle Exit after DNA Damage

Author

Segeren, Hendrika A., van Rijnberk, Lotte M., Moreno, Eva, Riemers, Frank M., van Liere, Elsbeth A., Yuan, Ruixue, Wubbolts, Richard, de Bruin, Alain, Westendorp, Bart, Pathobiologie, dPB RMSC, Chirurgie, dCSCA RMSC-1, LS Pathobiologie, IOV CCB, Celbiologie, dB&C I&I, Dep Biomolecular Health Sciences, CS_Locomotion, Pathobiologie, dPB RMSC, Chirurgie, dCSCA RMSC-1, LS Pathobiologie, IOV CCB, Celbiologie, dB&C I&I, Dep Biomolecular Health Sciences, and CS_Locomotion

Subjects
0301 basic medicine, DNA damage, Emi1, Biology, General Biochemistry, Genetics and Molecular Biology, live-cell imaging, single-cell RNA sequencing, tetraploidy, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Humans, cancer, E2F, Mitosis, lcsh:QH301-705.5, P53, Sequence Analysis, RNA, E2F transcription, DNA replication, anaphase-promoting complex/cyclosome, Cell cycle, Cell biology, E2F Transcription Factors, 030104 developmental biology, lcsh:Biology (General), Cancer cell, cell cycle, 030217 neurology & neurosurgery
Abstract

Summary: E2F transcription factors control the expression of cell-cycle genes. Cancers often demonstrate enhanced E2F target gene expression, which can be explained by increased percentages of replicating cells. However, we demonstrate in human cancer biopsy specimens that individual neoplastic cells display abnormally high levels of E2F-dependent transcription. To mimic this situation, we delete the atypical E2F repressors (E2F7/8) or overexpress the E2F3 activator in untransformed cells. Cells with elevated E2F activity during S/G2 phase fail to exit the cell cycle after DNA damage and undergo mitosis. In contrast, wild-type cells complete S phase and then exit the cell cycle by activating the APC/CCdh1 via repression of the E2F target Emi1. Many arrested wild-type cells eventually inactivate APC/CCdh1 to execute a second round of DNA replication and mitosis, thereby becoming tetraploid. Cells with elevated E2F transcription fail to exit the cell cycle after DNA damage, which potentially causes genomic instability, promotes malignant progression, and reduces drug sensitivity.

Published
2020

25. Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53

Author

Pathobiologie, dPB RMSC, Chirurgie, dCSCA RMSC-1, Dep Biomolecular Health Sciences, CS_Locomotion, Segeren, Hendrika A, van Liere, Elsbeth A, Riemers, Frank M, de Bruin, Alain, Westendorp, Bart, Pathobiologie, dPB RMSC, Chirurgie, dCSCA RMSC-1, Dep Biomolecular Health Sciences, CS_Locomotion, Segeren, Hendrika A, van Liere, Elsbeth A, Riemers, Frank M, de Bruin, Alain, and Westendorp, Bart

Published
2022

28. MUC13 negatively regulates tight junction proteins and intestinal epithelial barrier integrity via Protein Kinase C

Author

Infectiebiologie, Afd Biomol.Mass Spect. and Proteomics, Pathobiologie, Segui-Perez, Celia, Stapels, Daphne A.C., Ma, Ziliang, Su, Jinyi, Passchier, Elsemieke, Westendorp, Bart, Wu, Wei, Putten, Jos P.M. van, Strijbis, Karin, Infectiebiologie, Afd Biomol.Mass Spect. and Proteomics, Pathobiologie, Segui-Perez, Celia, Stapels, Daphne A.C., Ma, Ziliang, Su, Jinyi, Passchier, Elsemieke, Westendorp, Bart, Wu, Wei, Putten, Jos P.M. van, and Strijbis, Karin

Published
2022

29. Inhibition of polyploidization in Pten-deficient livers reduces steatosis

Author

Cell Biology, Metabolism and Cancer, Pathobiologie, CS_Locomotion, Veterinaire biochemie, Equine Musculoskeletal Biology, Dep Biomolecular Health Sciences, Moreno, Eva, Matondo, Augustine B, Bongiovanni, Laura, van de Lest, Chris H A, Molenaar, Martijn R, Toussaint, Mathilda J M, van Essen, Saskia C, Houweling, Martin, Helms, J Bernd, Westendorp, Bart, de Bruin, Alain, Cell Biology, Metabolism and Cancer, Pathobiologie, CS_Locomotion, Veterinaire biochemie, Equine Musculoskeletal Biology, Dep Biomolecular Health Sciences, Moreno, Eva, Matondo, Augustine B, Bongiovanni, Laura, van de Lest, Chris H A, Molenaar, Martijn R, Toussaint, Mathilda J M, van Essen, Saskia C, Houweling, Martin, Helms, J Bernd, Westendorp, Bart, and de Bruin, Alain

Published
2022

31. CDC6: A novel canine tumour biomarker detected in circulating extracellular vesicles

Author

dPB RMSC, dB&C I&I, Pathobiologie, Afd Pharmaceutics, Chirurgie, dCSCA AVR, Interne geneeskunde GD, dCSCA RMSC-2, Celbiologie, Dep Biomolecular Health Sciences, CS_Cancer, Andriessen, Anneloes, Bongiovanni, Laura, Driedonks, Tom A P, van Liere, Elsbeth, Seijger, Anne, Hegeman, Charlotte V, van Nimwegen, Sebastiaan A, Galac, Sara, Westendorp, Bart, Nolte-T Hoen, Esther N M, de Bruin, Alain, dPB RMSC, dB&C I&I, Pathobiologie, Afd Pharmaceutics, Chirurgie, dCSCA AVR, Interne geneeskunde GD, dCSCA RMSC-2, Celbiologie, Dep Biomolecular Health Sciences, CS_Cancer, Andriessen, Anneloes, Bongiovanni, Laura, Driedonks, Tom A P, van Liere, Elsbeth, Seijger, Anne, Hegeman, Charlotte V, van Nimwegen, Sebastiaan A, Galac, Sara, Westendorp, Bart, Nolte-T Hoen, Esther N M, and de Bruin, Alain

Published
2022

33. A reverse brake for the cell cycle.

Author

Westendorp, Bart

Subjects
*CELL cycle, *CELL division
Abstract

The article offers information on how cancer cells can undergo whole-genome doubling due to disruptions in cell cycle control pathways. Topics include the role of mitogenic signaling via cyclin-dependent kinases 4 and 6 (CDK4/6) in preventing cells from slipping back into the G1 phase; the role of the ubiquitin ligase APC/CCDH1 in ensuring DNA replication occurs only once per cell cycle; and the finding that stress-driven whole-genome doubling events can occur independently of the p53 pathway.

Published
2024
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34. CDC6 : A novel canine tumour biomarker detected in circulating extracellular vesicles

Author

Andriessen, Anneloes, primary, Bongiovanni, Laura, additional, Driedonks, Tom A. P., additional, van Liere, Elsbeth, additional, Seijger, Anne, additional, Hegeman, Charlotte V., additional, van Nimwegen, Sebastiaan A., additional, Galac, Sara, additional, Westendorp, Bart, additional, Nolte‐'t Hoen, Esther N. M., additional, and de Bruin, Alain, additional

Published
2021
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38. Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context

Author

Moreno, Eva, Pandit, Shusil K, Toussaint, Mathilda J M, Bongiovanni, Laura, Harkema, Liesbeth, van Essen, Saskia C, van Liere, Elsbeth A, Westendorp, Bart, de Bruin, Alain, LS Pathobiologie, dPB RMSC, Dutch Molecular Pathology Centre, Pathobiologie, Dep Biomolecular Health Sciences, LS Pathobiologie, dPB RMSC, Dutch Molecular Pathology Centre, Pathobiologie, and Dep Biomolecular Health Sciences

Subjects
0301 basic medicine, Genetically modified mouse, EXPRESSION, Cancer Research, Interaction, DNA repair, Repressor, interaction, Context (language use), ORGANIZATION, transgenic mice, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Transgenic mice, CELL-CYCLE, RETINOBLASTOMA PROTEIN, TRANSCRIPTION, E2F, Rb, RC254-282, ARREST, biology, MUTATIONS, Retinoblastoma protein, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cell cycle, GENE, Atypical E2Fs, atypical E2Fs, tumorigenesis, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, FAMILY-MEMBER, Tumorigenesis, ENTRY, Cancer research, biology.protein, biological phenomena, cell phenomena, and immunity, Carcinogenesis
Abstract

Simple SummaryIn virtually all human malignancies, the CDK-RB-E2F pathway is dysregulated resulting in the activation of the E2F transcriptional network. Rb and atypical E2Fs are the most important negative regulators of E2F-dependent transcription during tumorigenesis. However, it is unknown whether they cooporate or act independently in tumor development. Here we show that combined loss of RB and atypical E2Fs in mice enhances tumorigenesis in the liver, while in the pituitary gland, we observe inhibition of tumorigenesis. These findings suggest that the interaction between RB and atypical E2Fs in controlling tumorigenesis occurs in a tissue cell-type specific manner.E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and -8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently, it is unknown if and how RB and atypical E2Fs functionally interact in vivo. Here, we demonstrate that mice with liver-specific combinatorial deletion of Rb and E2f7/8 have reduced life-spans compared to E2f7/8 or Rb deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. In contrast, loss of either E2f7 or E2f8 largely prevented the formation of pituitary tumors in Rb+/- mice. To test whether atypical E2Fs can also function as oncogenes independent of RB loss, we induced long-term overexpression of E2f7 or E2f8 in mice. E2F7 and -8 overexpression increased the incidence of tumors in the lungs, but not in other tissues. Collectively, these data show that atypical E2Fs can promote but also inhibit tumorigenesis depending on tissue type and RB status. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency.

Published
2021

40. E2F7 is a potent inhibitor of liver tumor growth in adult mice

Author

Moreno, Eva, Toussaint, Mathilda J M, van Essen, Saskia C, Bongiovanni, Laura, van Liere, Elsbeth A, Koster, Mirjam H, Yuan, Ruixue, van Deursen, Jan, Westendorp, Bart, de Bruin, Alain, Pathobiologie, dPB RMSC, LS Pathobiologie, Dep Biomolecular Health Sciences, Pathobiologie, dPB RMSC, LS Pathobiologie, and Dep Biomolecular Health Sciences

Subjects
0301 basic medicine, Genetically modified mouse, Male, Transcriptional Activation, DNA damage, Transgene, Atypical E2Fs, liver cancer, transgenic mouse models, Apoptosis, Biology, medicine.disease_cause, 03 medical and health sciences, Mice, 0302 clinical medicine, E2F7 Transcription Factor, Liver Biology/Pathobiology, medicine, Animals, Humans, Cell Proliferation, Mice, Knockout, Hepatology, Cell growth, Cell Cycle, Liver Neoplasms, Retinoblastoma protein, DNA replication, Original Articles, Mice, Inbred C57BL, Repressor Proteins, 030104 developmental biology, Cancer research, biology.protein, Hepatocytes, 030211 gastroenterology & hepatology, Original Article, Carcinogenesis, DNA Damage, HeLa Cells
Abstract

Background and Aims Up-regulation of the E2F-dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F-dependent transcription. They are atypical in that they do not bind to dimerization partner proteins and are not controlled by retinoblastoma protein. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity in vivo have been lacking.Approach and Results Here, we generated transgenic mice with doxycycline-controlled transcriptional activation of E2f7 and E2f8 and induced their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of E2f7 and, to lesser extent, E2f8 transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage, and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity, and cell proliferation in diethylnitrosamine-induced liver tumors.Conclusion Collectively, our findings demonstrate that atypical E2Fs can override cell-cycle entry and progression governed by other E2F family members and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.

Published
2021

41. The glycosylated extracellular domain of MUC1 protects against SARS-CoV-2 infection at the respiratory surface

Author

Infectiebiologie, Virologie, Pathobiologie, dPB RMSC, Celbiologie, IOV CCB, dB&C I&I, dI&I I&I-1, dI&I I&I-2, Chatterjee, Maitrayee, Huang, Liane Z.X., Wang, Chunyan, Mykytyn, Anna Z., Westendorp, Bart, Wubbolts, Richard W., Bosch, Berend-Jan, Haagmans, Bart L., Putten, Jos P.M. van, Strijbis, Karin, Infectiebiologie, Virologie, Pathobiologie, dPB RMSC, Celbiologie, IOV CCB, dB&C I&I, dI&I I&I-1, dI&I I&I-2, Chatterjee, Maitrayee, Huang, Liane Z.X., Wang, Chunyan, Mykytyn, Anna Z., Westendorp, Bart, Wubbolts, Richard W., Bosch, Berend-Jan, Haagmans, Bart L., Putten, Jos P.M. van, and Strijbis, Karin

Published
2021

43. Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context

Author

LS Pathobiologie, dPB RMSC, Dutch Molecular Pathology Centre, Pathobiologie, Dep Biomolecular Health Sciences, Moreno, Eva, Pandit, Shusil K, Toussaint, Mathilda J M, Bongiovanni, Laura, Harkema, Liesbeth, van Essen, Saskia C, van Liere, Elsbeth A, Westendorp, Bart, de Bruin, Alain, LS Pathobiologie, dPB RMSC, Dutch Molecular Pathology Centre, Pathobiologie, Dep Biomolecular Health Sciences, Moreno, Eva, Pandit, Shusil K, Toussaint, Mathilda J M, Bongiovanni, Laura, Harkema, Liesbeth, van Essen, Saskia C, van Liere, Elsbeth A, Westendorp, Bart, and de Bruin, Alain

Published
2021

44. E2F7 is a potent inhibitor of liver tumor growth in adult mice

Author

Pathobiologie, dPB RMSC, LS Pathobiologie, Dep Biomolecular Health Sciences, Moreno, Eva, Toussaint, Mathilda J M, van Essen, Saskia C, Bongiovanni, Laura, van Liere, Elsbeth A, Koster, Mirjam H, Yuan, Ruixue, van Deursen, Jan, Westendorp, Bart, de Bruin, Alain, Pathobiologie, dPB RMSC, LS Pathobiologie, Dep Biomolecular Health Sciences, Moreno, Eva, Toussaint, Mathilda J M, van Essen, Saskia C, Bongiovanni, Laura, van Liere, Elsbeth A, Koster, Mirjam H, Yuan, Ruixue, van Deursen, Jan, Westendorp, Bart, and de Bruin, Alain

Published
2021

45. Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation

Author

Pathobiologie DMPC, dPB CR, Dep Biomolecular Health Sciences, Pathobiologie, dPB RMSC, Roukens, M Guy, Frederiks, Cynthia L, Seinstra, Danielle, Braccioli, Luca, Khalil, Antoine A, Pals, Cornelieke, De Neck, Simon, Bornes, Laura, Beerling, Evelyne, Mokry, Michal, de Bruin, Alain, Westendorp, Bart, van Rheenen, Jacco, Coffer, Paul J, Pathobiologie DMPC, dPB CR, Dep Biomolecular Health Sciences, Pathobiologie, dPB RMSC, Roukens, M Guy, Frederiks, Cynthia L, Seinstra, Danielle, Braccioli, Luca, Khalil, Antoine A, Pals, Cornelieke, De Neck, Simon, Bornes, Laura, Beerling, Evelyne, Mokry, Michal, de Bruin, Alain, Westendorp, Bart, van Rheenen, Jacco, and Coffer, Paul J

Published
2021

46. Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation

Author

CMM Groep Coffer, Infection & Immunity, Cancer, CMM Groep de Rooij, Onderzoek Medische Oncologie, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, CMM Sectie Stem Cells, Onderzoek, Regenerative Medicine and Stem Cells, Roukens, M Guy, Frederiks, Cynthia L, Seinstra, Danielle, Braccioli, Luca, Khalil, Antoine A, Pals, Cornelieke, De Neck, Simon, Bornes, Laura, Beerling, Evelyne, Mokry, Michal, de Bruin, Alain, Westendorp, Bart, van Rheenen, Jacco, Coffer, Paul J, CMM Groep Coffer, Infection & Immunity, Cancer, CMM Groep de Rooij, Onderzoek Medische Oncologie, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, CMM Sectie Stem Cells, Onderzoek, Regenerative Medicine and Stem Cells, Roukens, M Guy, Frederiks, Cynthia L, Seinstra, Danielle, Braccioli, Luca, Khalil, Antoine A, Pals, Cornelieke, De Neck, Simon, Bornes, Laura, Beerling, Evelyne, Mokry, Michal, de Bruin, Alain, Westendorp, Bart, van Rheenen, Jacco, and Coffer, Paul J

Published
2021

47. CDC6: A novel canine tumour biomarker detected in circulating extracellular vesicles.

Author

Andriessen, Anneloes, Bongiovanni, Laura, Driedonks, Tom A. P., van Liere, Elsbeth, Seijger, Anne, Hegeman, Charlotte V., van Nimwegen, Sebastiaan A., Galac, Sara, Westendorp, Bart, Nolte‐'t Hoen, Esther N. M., and de Bruin, Alain

Subjects
CIRCULATING tumor DNA, EXTRACELLULAR vesicles, CELL cycle proteins, GEL permeation chromatography, NUCLEIC acids, TUMORS, POLYMERASE chain reaction
Abstract

Circulating nucleic acids and extracellular vesicles (EV) represent novel biomarkers to diagnose cancer. The non‐invasive nature of these so‐called liquid biopsies provides an attractive alternative to tissue biopsy‐based cancer diagnostics. This study aimed to investigate if circulating cell cycle‐related E2F target transcripts can be used to diagnose tumours in canine tumour patients with different types of tumours. Furthermore, we assessed if these mRNAs are localised within circulating EV. We isolated total RNA from the plasma of 20 canine tumour patients and 20 healthy controls. Four E2F target genes (CDC6, DHFR, H2AFZ and ATAD2) were selected based on the analysis of published data of tumour samples available in public databases. We performed reverse transcription and quantitative real‐time PCR to analyse the plasma levels of selected E2F target transcripts. All four E2F target transcripts were detectable in the plasma of canine tumour patients. CDC6 mRNA levels were significantly higher in the plasma of canine tumour patients compared to healthy controls. A subset of canine tumour patient and healthy control plasma samples (n = 7) were subjected to size exclusion chromatography in order to validate association of the E2F target transcripts to circulating EV. For CDC6, EV analysis enhanced their detectability compared to total plasma analysis. In conclusion, our study reveals circulating CDC6 as a promising non‐invasive biomarker to diagnose canine tumours. [ABSTRACT FROM AUTHOR]

Published
2022
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48. E2F-Family Members Engage the PIDDosome to Limit Hepatocyte Ploidy in Liver Development and Regeneration

Author

Sladky, Valentina C., Knapp, Katja, Soratroi, Claudia, Heppke, Julia, Eichin, Felix, Rocamora-Reverte, Lourdes, Szabo, Tamas G., Bongiovanni, Laura, Westendorp, Bart, Moreno, Eva, van Liere, Elsbeth A., Bakker, Bjorn, Spierings, Diana C.J., Wardenaar, René, Pereyra, David, Starlinger, Patrick, Schultze, Simon, Trauner, Michael, Stojakovic, Tatjana, Scharnagl, Hubert, Fava, Luca L., Foijer, Floris, de Bruin, Alain, Villunger, Andreas, Pathobiologie, dPB RMSC, and Dep Biomolecular Health Sciences

Subjects
p53, caspases, regeneration, PIDDosome, polyploidy, liver development
Abstract

E2F transcription factors control the cytokinesis machinery and thereby ploidy in hepatocytes. If or how these proteins limit proliferation of polyploid cells with extra centrosomes remains unknown. Here, we show that the PIDDosome, a signaling platform essential for caspase-2-activation, limits hepatocyte ploidy and is instructed by the E2F network to control p53 in the developing as well as regenerating liver. Casp2 and Pidd1 act as direct transcriptional targets of E2F1 and its antagonists, E2F7 and E2F8, that together co-regulate PIDDosome expression during juvenile liver growth and regeneration. Of note, whereas hepatocyte aneuploidy correlates with the basal ploidy state, the degree of aneuploidy itself is not limited by PIDDosome-dependent p53 activation. Finally, we provide evidence that the same signaling network is engaged to control ploidy in the human liver after resection. Our study defines the PIDDosome as a primary target to manipulate hepatocyte ploidy and proliferation rates in the regenerating liver. Sladky et al. report a key role for the PIDDosome in regulating p53 activation to limit hepatocyte polyploidy during juvenile liver growth and regeneration. Expression of essential PIDDosome components is controlled by a E2F-family regulated circuitry. The study defines the PIDDosome as a putative target to enhance liver regeneration.

Published
2020

49. Excessive E2F Transcription in Single Cancer Cells Precludes Transient Cell-Cycle Exit after DNA Damage

Author

Pathobiologie, dPB RMSC, Chirurgie, dCSCA RMSC-1, LS Pathobiologie, IOV CCB, Celbiologie, dB&C I&I, Dep Biomolecular Health Sciences, CS_Locomotion, Segeren, Hendrika A., van Rijnberk, Lotte M., Moreno, Eva, Riemers, Frank M., van Liere, Elsbeth A., Yuan, Ruixue, Wubbolts, Richard, de Bruin, Alain, Westendorp, Bart, Pathobiologie, dPB RMSC, Chirurgie, dCSCA RMSC-1, LS Pathobiologie, IOV CCB, Celbiologie, dB&C I&I, Dep Biomolecular Health Sciences, CS_Locomotion, Segeren, Hendrika A., van Rijnberk, Lotte M., Moreno, Eva, Riemers, Frank M., van Liere, Elsbeth A., Yuan, Ruixue, Wubbolts, Richard, de Bruin, Alain, and Westendorp, Bart

Published
2020

50. PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis

Author

Pathobiologie, dPB RMSC, Dep Biomolecular Health Sciences, Sladky, Valentina C., Knapp, Katja, Szabo, Tamas G., Braun, Vincent Z., Bongiovanni, Laura, van den Bos, Hilda, Spierings, Diana C.J., Westendorp, Bart, Curinha, Ana, Stojakovic, Tatjana, Scharnagl, Hubert, Timelthaler, Gerald, Tsuchia, Kaoru, Pinter, Matthias, Semmler, Georg, Foijer, Floris, de Bruin, Alain, Reiberger, Thomas, Rohr-Udilova, Nataliya, Villunger, Andreas, Pathobiologie, dPB RMSC, Dep Biomolecular Health Sciences, Sladky, Valentina C., Knapp, Katja, Szabo, Tamas G., Braun, Vincent Z., Bongiovanni, Laura, van den Bos, Hilda, Spierings, Diana C.J., Westendorp, Bart, Curinha, Ana, Stojakovic, Tatjana, Scharnagl, Hubert, Timelthaler, Gerald, Tsuchia, Kaoru, Pinter, Matthias, Semmler, Georg, Foijer, Floris, de Bruin, Alain, Reiberger, Thomas, Rohr-Udilova, Nataliya, and Villunger, Andreas

Published
2020

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