A5068417067- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- DNA Repair Mechanisms
- RNA modifications and cancer
- Acute Myeloid Leukemia Research
- Genetics and Neurodevelopmental Disorders
- Nuclear Structure and Function
- Neuroblastoma Research and Treatments
- Protein Degradation and Inhibitors
- Ocular Oncology and Treatments
- Lung Cancer Treatments and Mutations
- Chronic Myeloid Leukemia Treatments
- interferon and immune responses
- Water Treatment and Disinfection
- Multiple Myeloma Research and Treatments
- Epigenetics and DNA Methylation
- Heat shock proteins research
- PI3K/AKT/mTOR signaling in cancer
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- FOXO transcription factor regulation
- Sirtuins and Resveratrol in Medicine
- Telomeres, Telomerase, and Senescence
- Viral gastroenteritis research and epidemiology
- Carcinogens and Genotoxicity Assessment
- Endoplasmic Reticulum Stress and Disease
Leiden University Medical Center
2011-2025
Leiden University
1985-2023
Vesuvius (United Kingdom)
1987
Stichting Artsenlaboratorium en Trombosedienst
1986
Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms chemotherapy immunotherapy, leading 5-year survival rate 9%. Our study aims add novel small molecule therapeutics for treatment PDAC.We have studied whether TAK-981, highly selective potent inhibitor ubiquitin like modifier (SUMO) activating enzyme E1 could be used treat preclinical syngeneic PDAC mouse...
Small ubiquitin-like modifiers play critical roles in the DNA damage response (DDR). To increase our understanding of SUMOylation mammalian DDR, we employed a quantitative proteomics approach order to identify dynamically regulated SUMO-2 conjugates and modification sites upon treatment with damaging agent methyl methanesulfonate (MMS). We have uncovered dynamic set 20 upregulated 33 downregulated conjugates, 755 sites, which 362 were MMS. In contrast yeast, where is centered on homologous...
SUMO-targeted ubiquitin ligases (STUbLs) mediate the ubiquitylation of SUMOylated proteins to modulate their functions. In search direct targets for STUbL RNF4, we have developed TULIP (targets identified by proteomics) covalently trap E3 ligases. methodology could be widely employed delineate substrate wiring. Here report that single SUMO E2 Ubc9 and PIAS1, PIAS2, PIAS3, ZNF451, NSMCE2 are RNF4 targets. We confirm PIAS1 as a key substrate. Furthermore, establish ligase BARD1, tumor...
We have previously demonstrated that in non-oncogenic adenovirus-transformed baby rat kidney cells a complex of hsp27 and 22-kDa protein is present, which lacking oncogenic (Zantema, A., de Jong, E., Lardenoije, R., van der Eb, A. J. (1989) Virol. 63, 3368-3375). Here we show the identical to alpha B-crystallin. The B-crystallin also found some other (non-transformed) cells. However, most tested only no synthesized. Gel filtration studies both proteins are present almost exclusively 700-kDa...
Abstract In contrast to our extensive knowledge on ubiquitin polymer signaling, we are severely limited in understanding of poly-SUMO signaling. We set out identify substrates conjugated SUMO polymers, using knockdown the poly-SUMO2/3 protease SENP6. over 180 SENP6 regulated proteins that represent highly interconnected functional groups including constitutive centromere-associated network (CCAN), CENP-A loading factors Mis18BP1 and Mis18A DNA damage response factors. Our results indicate a...
The SUMO protease SENP6 maintains genomic stability, but mechanistic understanding of this process remains limited. We find that deconjugates SUMO2/3 polymers on a group DNA damage response proteins, including BRCA1-BARD1, 53BP1, BLM and ERCC1-XPF. these proteins in hypo-SUMOylated state under unstressed conditions counteracts their polySUMOylation after hydroxyurea-induced stress. Co-depletion RNF4 leads to further increase SUMOylation BRCA1, BARD1 BLM, suggesting antagonizes targeting by...
The DNA from various human tumors and tumor cell lines was screened for the presence of mutated ras oncogenes with synthetic oligonucleotide probes, as well NIH/3T3 transfection assay. Among mutations found we discovered two novel Ki- in codon 12: gly to ala ser. A gastric carcinoma possess a single Ki-ras allele (gly-12 ser), 30–50 fold amplified normal allele. This implies that activating steps must have occurred this malignancy.
The p53 regulatory network is critically involved in preventing the initiation of cancer. In unstressed cells, maintained at low levels and largely inactive, mainly through action its two essential negative regulators, HDM2 HDMX. abundance activity are up-regulated response to various stresses, including DNA damage oncogene activation. Active initiates transcriptional transcription-independent programs that result cell cycle arrest, cellular senescence, or apoptosis. also activates...
Abstract Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of to preserve transcriptional output and thereby cellular homeostasis counteract aging. TC-NER is initiated the stalling RNA polymerase II at lesions, triggers assembly TC-NER-specific proteins CSA, CSB UVSSA. WD40-repeat containing protein, substrate receptor subunit cullin-RING ubiquitin ligase complex composed DDB1, CUL4A/B...
The best-characterized mode of noncovalent SUMO interaction involves binding a SUMO-interaction motif (SIM) to conserved groove in SUMO. Our knowledge on other types interactions is still limited. Using SIM-binding SUMO2/3 mutants and mass spectrometry, we identified proteins that bind an alternate manner. Domain-enrichment analysis characterized group WD40 repeat domain–containing as SIM-independent interactors, validated direct SEC13 SEH1L vitro . AlphaFold-3 modeling mutational analysis,...
Abstract Background In around 50% of all human cancers the tumor suppressor p53 is mutated. It generally assumed that in remaining tumors wild-type protein functionally impaired. The two main inhibitors p53, hMDM2 (MDM2) and hMDMX (MDMX/MDM4) are frequently overexpressed tumors. Whereas activity to degrade protein, its close homolog does not but it represses transcriptional activity. Here we study role neoplastic transformation fibroblasts embryonic retinoblasts, since a high number...
Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of to preserve transcriptional output and thereby cellular homeostasis counteract aging. TC-NER is initiated the stalling RNA polymerase II at lesions, triggers assembly TC-NER-specific proteins CSA, CSB UVSSA. WD40-repeat containing protein, substrate receptor subunit cullin-RING ubiquitin ligase complex composed DDB1, CUL4A/B RBX1 (CRL4