A5018097630- Cancer-related gene regulation
- RNA modifications and cancer
- Genomic variations and chromosomal abnormalities
- Cancer-related molecular mechanisms research
- Genetic factors in colorectal cancer
- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- Circular RNAs in diseases
- Cholangiocarcinoma and Gallbladder Cancer Studies
- DNA Repair Mechanisms
- Microtubule and mitosis dynamics
- MicroRNA in disease regulation
- Chromosomal and Genetic Variations
- Colorectal Cancer Treatments and Studies
- Cancer-related Molecular Pathways
- Acute Lymphoblastic Leukemia research
- Genomics and Chromatin Dynamics
- Biochemical and Molecular Research
- Prenatal Screening and Diagnostics
- Molecular Biology Techniques and Applications
- Carcinogens and Genotoxicity Assessment
- CRISPR and Genetic Engineering
- RNA Research and Splicing
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
National Institutes of Health
2009-2024
National Cancer Institute
2012-2024
Center for Cancer Research
2004-2023
University of Copenhagen
2012
Lund University
2012
National Institute of Allergy and Infectious Diseases
2002-2006
The University of Texas Southwestern Medical Center
2006
Universitätsmedizin Göttingen
2005
Baylor College of Medicine
2004
Karolinska Institutet
2004
Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage. Double-strand breaks (DSBs) induce histone H2AX phosphorylation, which is associated with recruitment factors damaged DNA. To help clarify physiological role H2AX, we targeted in mice. Although not essential for irradiation-induced cell-cycle checkpoints, H2AX-/- mice were radiation sensitive, growth retarded, immune deficient, mutant males infertile. These pleiotropic phenotypes chromosomal...
Antibodies against nuclear self-antigens are characteristic of systemic autoimmunity, although mechanisms promoting their generation and selection unclear. Here, we report that B cells containing the Y-linked autoimmune accelerator ( Yaa ) locus intrinsically biased toward nucleolar antigens because increased expression TLR7, a single-stranded RNA-binding innate immune receptor. The TLR7 gene is duplicated in mice 4-Megabase expansion pseudoautosomal region. These results reveal high...
A system for tetracycline-regulated inducible gene expression was described recently which relies on constitutive of a tetracycline-controlled transactivator (tTA) fusion protein combining the tetracycline repressor and transcriptional activation domain VP16 [Gossen, M. & Bujard, H. (1992) Proc. Natl. Acad. Sci. USA 89, 5547-5551]. This yielded only low levels protein, probably because tTA is toxic. To avoid this difficulty, we placed under control promoter to binds, making itself...
There is a wide spectrum of tumor responsiveness rectal adenocarcinomas to preoperative chemoradiotherapy ranging from complete response resistance. This study aimed investigate whether parallel gene expression profiling the primary can contribute stratification patients into groups responders or nonresponders.Pretherapeutic biopsies 30 locally advanced carcinomas were analyzed for signatures using microarrays. All participants phase III clinical trial (CAO/ARO/AIO-94, German Rectal Cancer...
Genetic disorders affecting cellular responses to DNA damage are characterized by high rates of translocations involving antigen receptor loci and increased susceptibility lymphoid malignancies. We report that the Nijmegen breakage syndrome protein (NBS1) histone gamma-H2AX, which associate with irradiation-induced double-strand breaks (DSBs), also found at sites VDJ (variable, diversity, joining) recombination-induced DSBs. In developing thymocytes, NBS1 gamma-H2AX form nuclear foci...
Measurement of the nuclear DNA content allows classification human cancers as either diploid or aneuploid. To gain further insight into mechanisms aneuploidy, we compared cytogenetic profile mismatch-repair-deficient versus mismatch-repair-proficient aneuploid colorectal carcinoma cell lines using comparative genomic hybridization and spectral karyotyping. Aneuploid carcinomas revealed an average 19 chromosomal imbalances per line. Such numerical aberrations were exceedingly scarce in...
A systems approach is being applied in many areas of the biological sciences, particularly cancer research. The coordinated, simultaneous extraction DNA, RNA, and proteins from a single sample crucial for accurate correlations between genomic aberrations their consequences on transcriptome proteome. We present an to extract completely solubilize up 98% total protein recovered archived samples following TRIzoL isolation RNA DNA. also demonstrate using polyacrylamide gel electrophoresis (PAGE)...
Nonreciprocal translocations and gene amplifications are commonly found in human tumors. Although little is known about the mechanisms leading to such aberrations, tissue culture models predict that they can arise from DNA breakage, followed by cycles of chromatid fusion, asymmetric mitotic replication. Mice deficient both a nonhomologous end joining (NHEJ) repair protein p53 tumor suppressor develop lymphomas at an early age harboring amplification IgH/c-myc fusion. Here we report these...
Recent studies have demonstrated that DNA cleavage during V(D)J recombination is mediated by the RAG1 and RAG2 proteins. These proteins must therefore bind to signals, but specific binding interaction has been difficult study in vitro. Here, we use an vivo one-hybrid assay demonstrate RAG1, absence of RAG2, can mediate signal recognition via nonamer, with heptamer acting enhance its binding. A region sequence similarity bacterial invertases essential for Localization dependent upon presence...
Abstract Chromosomal aneuploidies are observed in essentially all sporadic carcinomas. These result tumor-specific patterns of genomic imbalances that acquired early during tumorigenesis, continuously selected for and faithfully maintained cancer cells. Although the paradigm translocation induced oncogene activation hematologic malignancies is firmly established, it not known how affect chromosome-specific gene expression particular chromosomal aneuploidy dysregulates genetic equilibrium...
miRNAs play a prominent role in variety of physiologic and pathologic biologic processes, including cancer. For rectal cancers, only limited data are available on miRNA expression profiles, whereas the underlying genomic transcriptomic aberrations have been firmly established. We therefore, aimed to comprehensively map patterns this disease.Tumor biopsies corresponding matched mucosa samples were prospectively collected from 57 patients with locally advanced cancers. Total RNA was extracted,...
MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression by inhibiting translation or promoting degradation of specific target messenger RNAs (mRNAs). Alteration the levels a number miRNAs is common in solid and hematological tumors. We have shown previously that miR-214 regulates Ezh2 skeletal muscle embryonic stem cells. The current study was aimed at examining role breast cancer where reduced but whether this phenomenon bears functional relevance unknown. MiR-214...
Hepatitis B virus (HBV) includes an X gene (HBx gene) that plays a critical role in liver carcinogenesis. Because centrosome abnormalities are associated with genomic instability most human cancer cells, we examined the effect of HBx on centrosomes. We found induced supernumerary centrosomes and multipolar spindles. This was independent mutations p21 gene. Furthermore, ability HBV to induce dependent presence physiological expression. recently showed induces cytoplasmic sequestration Crm1,...
Abstract To characterize patterns of global transcriptional deregulation in primary colon carcinomas, we did gene expression profiling 73 tumors [Unio Internationale Contra Cancrum stage II (n = 33) and III 40)] using oligonucleotide microarrays. For 30 the tumors, profiles were compared with those from matched normal mucosa samples. We identified a set 1,950 genes highly significant between samples (P < 1e−7). A proportion these mapped to chromosome 20 0.01). Seventeen had...
Abstract Chromosomal copy number alterations (aneuploidy) define the genomic landscape of most cancer cells, but identification oncogenic drivers behind these imbalances remains an unfinished task. In this study, we conducted a systematic analysis colorectal carcinomas that integrated changes and gene expression profiles. This revealed 44 highly overexpressed genes mapping to localized amplicons on chromosome 13, gains which occur often in cancers (CRC). RNA interference (RNAi)–mediated...
Abstract Genomic aberrations on chromosome 8 are common in colon cancer, and associated with lymph node distant metastases as well disease susceptibility. This prompted us to generate a high-resolution map of genomic imbalances 51 primary carcinomas using custom-designed array consisting tiling path BAC clones. analysis confirmed the dominant role this chromosome. Unexpectedly, position breakpoints suggested colocalization structural variants human genome. In order these sites increased...
To evaluate the mechanisms and consequences of chromosomal aberrations in colorectal cancer (CRC), we used a combination spectral karyotyping, array comparative genomic hybridization (aCGH), array-based global gene expression profiling on 31 primary carcinomas 15 established cell lines. Importantly, aCGH showed that profiles tumors are recapitulated We revealed preponderance chromosome breakpoints at sites copy number variants (CNVs) CRC lines, novel mechanism DNA breakage cancer. The...
Abstract In defining the genetic profiles in cancer, cytogenetically aberrant cell lines derived from primary tumors are important tools for study of carcinogenesis. Here, we present results a comprehensive investigation 15 established colorectal cancer using spectral karyotyping (SKY), fluorescence situ hybridization, and comparative genomic hybridization (CGH). Detailed karyotypic analysis by SKY on five (P53HCT116, T84, NCI‐H508, NCI‐H716, SK‐CO‐1) is described here first time. The with...
Abstract Background Colorectal carcinomas (CRC) carry massive genetic and transcriptional alterations that influence multiple cellular pathways. The study of proteins whose loss-of-function (LOF) alters the growth CRC cells can be used to further understand processes cancer depend upon for survival. Results A small-scale RNAi screen ~400 genes conducted in SW480 identified several candidate as required viability cells, most prominently CASP8AP2 / FLASH . To function this gene maintaining an...
TH2 clones may produce very variable amounts of IL-4. Among six prepared from homozygous or heterozygous mice in which Gfp replaced the first exon Il4, a range patterns CpG methylation Il4/Il13 locus was observed correlating with degree expression IL-4 green fluorescence protein. Patterns histone acetylation also showed differences between "high" and "low" clones. These results indicate that cells Il4 display chromatin accessibility associated distinct degrees expression. This finding...