Hans-dieter Royer - Academia.edu (original) (raw)
Papers by Hans-dieter Royer
Hodgkin’s disease is histopathologically characterized by the relative scarcity of neoplastic Hod... more Hodgkin’s disease is histopathologically characterized by the relative scarcity of neoplastic Hodgkin and Reed-Sternberg cells and for yet unknown reasons by an abundant reactive background of T lymphocytes and often eosinophils. Eotaxin is a CC-chemokine attracting eosinophils and T helper 2 (Th2) cells in allergic inflammation. We now report that eotaxin is strongly expressed in fibroblasts of Hodgkin’s disease tissues, whereas Hodgkin/Reed-Sternberg cells do not express this chemokine. In tissue culture, Hodgkin’s disease tumor cells induce eotaxin expression in cocultured dermal fibroblasts in a concentration leading to a specific chemotactic response of a Th2 cell clone. Production of tumor necrosis factor-a (TNF-a) by Hodgkin/Reed-Sternberg cells appears to be responsible for this induction, because blocking of TNF-a by neutralizing antibodies prevented
Journal of Clinical Oncology, 2007
563 Background: Y-box binding protein (YB-1), known as oncogenic transcription factor, is associa... more 563 Background: Y-box binding protein (YB-1), known as oncogenic transcription factor, is associated with up-regulation of MDR1, alters p53 function, and induces growth of an aggressive phenotype. In high-risk breast cancer, the prospective randomized WSG-AM-01 trial has reported significantly better event-free (EFS) and overall survival (OS) for tandem high-dose (HD) vs. dose-dense (DD) chemotherapy, especially in basal-like und HER2 subgroups. The present study examines the interaction of a drug resistant phenotype induced by YB-1 within the WSG-AM-01 collective at 5-year follow-up. Methods: 236 tumors (116 HD/120 DD) of 403 randomized patients (60%) were available for construction of tissue microarrays and determination of molecular classification by k-clustering of expression of 34 protein markers. Immunostaining of YB-1 by specific peptide antibody was scored semiquatitatively by intensity. Associations of YB-1 staining with other protein expression factors were studied by Pear...
Zeitschrift für Naturforschung C, 1978
Hepatitis A-Yirus-Single-Sranded D N A , Electron Microscopy, Length Measurements, Parvovirus Hep... more Hepatitis A-Yirus-Single-Sranded D N A , Electron Microscopy, Length Measurements, Parvovirus Hepatitis A-virus was purified from human stools by three purification steps. Virus was identified by radioimmuno-assay and purity monitored with immune electron microscopy. Virus particles, serologically and morphologically identical, banded in CsCl in two density ranges at 1.31 — 1.34 g/cm3 and at 1.41 — 1.43 g/cm3. Virions of density 1.31 — 1.34 g/cm3 were shown to contain single-stranded D N A of different size classes. Class I 1.33 kb, class I I 4.61 kb in addition a small amount of molecules was de tected with lengths up to 15 kb.
The Biology of Idiotypes, 1984
In his original proposal of an immunoregulatory network of lymphocytes, Jerne proposed that the n... more In his original proposal of an immunoregulatory network of lymphocytes, Jerne proposed that the naive immune system is in a negatively regulated state.(1) Before the introduction of antigen, a lymphocyte specific for a certain antigenic determinant (epitope) is held in check by another lymphocyte’s anti-idiotypic receptor. In this network all antibodies represent anti-idiotypes. The appearance of antigen perturbs this homeostatic down-regulation and an immune response is generated. As a consequence of the immune response to the individual epitopes, the amount of antigen is reduced below a threshold level whereupon the systems returns to homeostasis. In recent years, the mechanism by which the immune response is regulated has been investigated. Antigen-specific(2) and nonspecific(3) T-suppressor (Ts) cells play a critical role in this regulation. Further, idiotype-anti-idiotype interactions may be important in both Ts—target cell and Ts—Ts interactions. However, rather than existing in a down-regulated state before the appearance of an antigen, the immune system can be thought of as a complex set of dynamically activated and regulated cellular elements. Antigen stimulates an immune response (postive) and then initiates immunoregulatory (negative) events, instead of simply perturbing homeostatic regulation. Differential antigen presentation to T-helper (Th) and Ts cells by specific antigen-presenting cells (APCs) may shift this delicate balance from immunity to immune regulation. It appears that presentation of antigen by an I-A+ I-J− APC activates Th(4) cells, while an I-J+ I-A− APC activates Ts cells.(5) Moreover, differential expression of I-A- or I-J- encoded molecules on APCs might mediate these processes. On the other hand, T-cell idiotypes may serve as cell interaction molecules in immunoregulatory events subsequent to Ts activation.(6)
![Research paper thumbnail of NF546 [4,4′-(Carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)-carbonylimino))-bis(1,3-xylene-α,α′-diphosphonic Acid) Tetrasodium Salt] Is a Non-Nucleotide P2Y11 Agonist and Stimulates Release of Interleukin-8 from Human Monocyte-Derived Dendritic Cells](https://attachments.academia-assets.com/99741381/thumbnails/1.jpg)
](Journal of Pharmacology and Experimental Therapeutics, 2009
NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)carbonylimino)... more NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)carbonylimino))-bis(1,3-xylene-α,α'-diphosphonic acid) tetrasodium salt] is a nonnucleotide P2Y 11 agonist and stimulates release of IL-8 from human monocyte-derived dendritic cells
Journal of Experimental Medicine, 1985
The chromosomal location of Ti alpha was determined by hybridization of a radiolabeled cDNA for t... more The chromosomal location of Ti alpha was determined by hybridization of a radiolabeled cDNA for the alpha chain of human T cell receptor with 12 human X mouse cell hybrid DNAs cleaved with BamHI. Seven hybrids contained human Ti alpha, while the remaining five lacked it. Only human chromosome 14 matched the distribution of human Ti alpha signal across the mapping panel. Hybrids segregating a chromosome 14 translocation were used to demonstrate that Ti alpha is in the region 14pter greater than 14q21. Thus, the alpha and beta chain genes that contribute structural components to the Ti moiety of the human T cell receptor lie on different chromosomes. In humans, the immunoglobulin heavy chain locus and Ti alpha are in different regions of chromosome 14, with Ti alpha more proximal and the immunoglobulin heavy chain locus more distal.
Cancer Research, 2010
Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >... more Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >40% of breast cancers, where it is associated with poor prognosis, disease recurrence, and drug resistance. We questioned whether this may be linked to the ability of YB-1 to induce the expression of genes linked to cancer stem cells such as CD44 and CD49f. Herein, we report that YB-1 binds the CD44 and CD49f promoters to transcriptionally upregulate their expressions. The introduction of wild-type (WT) YB-1 or activated P-YB-1S102 stimulated the production of CD44 and CD49f in MDA-MB-231 and SUM 149 breast cancer cell lines. YB-1–transfected cells also bound to the CD44 ligand hyaluronan more than the control cells. Similarly, YB-1 was induced in immortalized breast epithelial cells and upregulated CD44. Conversely, silencing YB-1 decreased CD44 expression as well as reporter activity in SUM 149 cells. In mice, expression of YB-1 in the mammary gland induces CD44 and CD49f with associat...
This article cites 55 articles, 19 of which can be accessed free
Current knowledge about molecular mechanisms underlying disease progression and drug resistance i... more Current knowledge about molecular mechanisms underlying disease progression and drug resistance in multiple myeloma (MM) is still limited. Here, we analyzed the potential pathogenetic role of the Y box binding protein YB-1 in MM. YB-1 is a member of the cold shock domain protein superfamily and involved in various cellular functions like proliferation. Immunohistochemical analyses revealed that neither normal bone marrow (BM) plasma cells (PCs), premalignant PCs of patients with monoclonal gammopathy of unknown significance (MGUS) nor MM cells with a mature morphology showed expression of YB-1 in situ . In contrast, YB-1 was strongly expressed in situ in normal PC precursor blasts as well as in a MM subset and in vitro in all of the evaluated MM cell lines. The YB-1 expressing MM cells were characterized by an immature morphology and a highly proliferative phenotype as defined by Ki 67 expression. We observed that siRNA-mediated knockdown of YB-1 decreased proliferation and induced ...
Biochemical Pharmacology, 2015
Tinzaparin overcomes the proteoglycan-mediated cisplatin resistance in A2780cis cells by a transc... more Tinzaparin overcomes the proteoglycan-mediated cisplatin resistance in A2780cis cells by a transcriptional reprogramming, thus supporting cisplatin induced apoptosis.
Journal of Biological Chemistry, 2003
The multifunctional DNA-and RNA-associated Y-box protein 1 (YB-1) specifically binds to splicing ... more The multifunctional DNA-and RNA-associated Y-box protein 1 (YB-1) specifically binds to splicing recognition motifs and regulates alternative splice site selection. Here, we identify the arginine/serine-rich SRp30c protein as an interacting protein of YB-1 by performing a two-hybrid screen against a human mesangial cell cDNA library. Co-immunoprecipitation studies confirm a direct interaction of tagged proteins YB-1 and SRp30c in the absence of RNA via two independent protein domains of YB-1. A high affinity interaction is conferred through the N-terminal region. We show that the subcellular YB-1 localization is dependent on the cellular SRp30c content. In proliferating cells, YB-1 localizes to the cytoplasm, whereas FLAG-SRp30c protein is detected in the nucleus. After overexpression of YB-1 and FLAG-SRp30c, both proteins are co-localized in the nucleus, and this requires the N-terminal region of YB-1. Heat shock treatment of cells, a condition under which SRp30c accumulates in stress-induced Sam68 nuclear bodies, abrogates the co-localization and YB-1 shuttles back to the cytoplasm. Finally, the functional relevance of the YB-1/SRp30c interaction for in vivo splicing is demonstrated in the E1A minigene model system. Here, changes in splice site selection are detected, that is, overexpression of YB-1 is accompanied by preferential 5 splicing site selection and formation of the 12 S isoform.
Journal of Biological Chemistry, 2003
Expression of the Y-box protein YB-1 is increased in proliferating normal and cancer cells, but i... more Expression of the Y-box protein YB-1 is increased in proliferating normal and cancer cells, but its role in cell proliferation and cell cycle progression is unclear. We have identified a cell cycle-dependent relocalization of YB-1 from the cytoplasm to the nucleus at the G 1 /S phase transition and demonstrate that both the charged zipper and the cold shock domain are involved in regulating this process. Using cell lines that constitutively overexpress YB-1, we show that nuclear accumulation of YB-1 is associated with increased cyclin A and cyclin B1 mRNA and protein expression. We provide evidence that deregulated YB-1 expression is linked to adhesion-independent cell proliferation through the induction of cyclin A. Thus, we have identified YB-1 as a cell cycle stage-specific transcription factor important for cell proliferation. Y-box proteins belong to a family of evolutionary conserved proteins, which function as transcription factors, regulators of RNA metabolism, and protein synthesis (reviewed in Refs. 1 and 2). Y-box proteins might play important developmental roles in early embryogenesis (3). In non-dividing germ cells, Y-box proteins regulate the utilization of maternal and paternal stores of mRNA by the translational machinery (4-7). YB-1 was first identified as a DNA-binding protein that interacts with the Y-box sequence in major histocompatibility complex class II promoters (8). High levels of YB-1 are present in human fetal tissues of the heart, muscle, liver, lung, adrenal gland, and the brain (9). In contrast, the YB-1 expression patterns in most adult human tissues are unknown. A role of Y-box proteins in regulation of cell proliferation has been discussed, and high expression of Y-box proteins occurs under conditions of cell proliferation, e.g. in certain embryonal tissues, in fetal liver, in the regenerating liver after tissue damage (10), and in the proliferating compartment of colorectal mucosa (11). YB-1
Cancer Research, 2009
Platinum plays a central role in the therapy of ovarian cancer, and the emergence of platinum res... more Platinum plays a central role in the therapy of ovarian cancer, and the emergence of platinum resistance is a major obstacle for clinical management of the disease. We treated A2780 ovarian cancer cells by weekly cycles of cisplatin over a period of 6 months and unveiled that enhanced insulin-like growth factor I receptor (IGF-IR) expression and autocrine IGF-I are associated with hyperactivation of the IGF-IR and phosphatidylinositol-3-OH kinase (PI3K) pathways in cisplatin-resistant cells. IGF-IR expression levels increased during treatment cycles and correlated with cisplatin resistance. Purified IGF-I induced cisplatin resistance in diverse ovarian cancer cell lines, and small molecule inhibitors proved that IGF-IR and PI3K are essential for cisplatin resistance. Similar results were obtained with BG-1 ovarian cancer cells. Cytogenetic and array comparative genomic hybridization analyses revealed selection and de novo formation of chromosomal alterations during resistance develo...
Human Molecular Genetics, 2014
The WT1 gene encodes a zinc finger transcription factor important for normal kidney development. ... more The WT1 gene encodes a zinc finger transcription factor important for normal kidney development. WT1 is a suppressor for Wilms tumour development and an oncogene for diverse malignant tumours. We recently established cell lines from primary Wilms tumours with different WT1 mutations. To investigate the function of mutant WT1 proteins, we performed WT1 knockdown experiments in cell lines with a frameshift/extension (p.V432fsX87 5 Wilms3) and a stop mutation (p.P362X 5 Wilms2) of WT1, followed by genome-wide gene expression analysis. We also expressed wild-type and mutant WT1 proteins in human mesenchymal stem cells and established gene expression profiles. A detailed analysis of gene expression data enabled us to classify the WT1 mutations as gain-of-function mutations. The mutant WT1 Wilms2 and WT1 Wilms3 proteins acquired an ability to modulate the expression of a highly significant number of genes from the G2/M phase of the cell cycle, and WT1 knockdown experiments showed that they are required for Wilms tumour cell proliferation. p53 negatively regulates the activity of a large number of these genes that are also part of a core proliferation cluster in diverse human cancers. Our data strongly suggest that mutant WT1 proteins facilitate expression of these cell cycle genes by antagonizing transcriptional repression mediated by p53. We show that mutant WT1 can physically interact with p53. Together the findings show for the first time that mutant WT1 proteins have a gain-of-function and act as oncogenes for Wilms tumour development by regulating Wilms tumour cell proliferation.
Human Molecular Genetics, 2010
Wilms tumors (WTs) are genetically heterogeneous kidney tumors whose cells of origin are unknown.... more Wilms tumors (WTs) are genetically heterogeneous kidney tumors whose cells of origin are unknown. Tumors with WT1 mutations and concomitant loss of the wild-type allele represent a distinct subgroup, frequently associated with mutations in CTNNB1. Here, we describe the establishment and characterization of long-term cell cultures derived from five individual WTs with WT1 mutations. Three of these tumor cell lines also had CTNNB1 mutations and an activated canonical Wnt signaling pathway as measured by b-catenin/ T cell-specific transcription factor (TCF) transcriptional activity. Four of the five Wilms cell lines had a stable normal karyotype for at least 25 passages, and four lines showed loss of heterozygosity of chromosome 11p due to mitotic recombination in 11p11. Gene expression profiling revealed that the WT cell lines are highly similar to human mesenchymal stem cells (MSCs) and FACS analysis demonstrated the expression of MSCspecific surface proteins CD105, CD90 and CD73. The stem cell like nature of the WT cells is further supported by their adipogenic, chondrogenic, osteogenic and myogenic differentiation potentials. By generating multipotent mesenchymal precursors from paraxial mesoderm (PAM) in tissue culture using embryonal stem cells, gene expression profiles of PAM and MSCs were described. Using these published gene sets, we found coexpression of a large number of genes in WT cell lines, PAM and MSCs. Lineage plasticity is indicated by the simultaneous expression of genes from the mesendodermal and neuroectodermal lineages. We conclude that WTs with WT1 mutations have specific traits of PAM, which is the source of kidney stromal cells.
Journal of Biological Chemistry, 2006
Journal of Biological Chemistry, 2007
The use of platinum complexes for the therapy of breast cancer is an emerging new treatment modal... more The use of platinum complexes for the therapy of breast cancer is an emerging new treatment modality. To gain insight into the mechanisms underlying cisplatin resistance in breast cancer, we used estrogen receptor-positive MCF-7 cells as a model system. We generated cisplatin-resistant MCF-7 cells and determined the functional status of epidermal growth factor receptor (EGFR), MAPK, and AKT signaling pathways by phosphoreceptor tyrosine kinase and phospho-MAPK arrays. The cisplatinresistant MCF-7 cells are characterized by increased EGFR phosphorylation, high levels of AKT1 kinase activity, and ERK1 phosphorylation. In contrast, the JNK and p38 MAPK modules of the MAPK signaling pathway were inactive. These conditions were associated with inactivation of the p53 pathway and increased BCL-2 expression. We investigated the expression of genes encoding the ligands for the ERBB signaling cascade and found a selective up-regulation of amphiregulin expression, which occurred at later stages of cisplatin resistance development. Amphiregulin is a specific ligand of the EGFR (ERBB1) and a potent mitogen for epithelial cells. After exposure to cisplatin, the resistant MCF-7 cells secreted amphiregulin protein over extended periods of time, and knockdown of amphiregulin expression by specific short interfering RNA resulted in a nearly complete reversion of the resistant phenotype. To demonstrate the generality and importance of our findings, we examined amphiregulin expression and cisplatin resistance in a variety of human breast cancer cell lines and found a highly significant correlation. In contrast, amphiregulin levels did not significantly correlate with cisplatin resistance in a panel of lung cancer cell lines. We have thus identified a novel function of amphiregulin for cisplatin resistance in human breast cancer cells.
T cell receptors for antigen and major histocompatibility complex (MHC) ~ determinants have, usin... more T cell receptors for antigen and major histocompatibility complex (MHC) ~ determinants have, using anticlonotypic monoclonal antibodies (mAb), been defined on inducer, suppressor, and class I and class II MHC-specific cytotoxic T lymphocytes as T3oassociated molecules of 90 kilodaltons (kD) molecular mass (1-8). These cionotypic structures, termed Ti, are comprised of one 49-54 kD a and one 43 kD/3 subunit, which are disulfide linked. Peptide mapping analysis of isolated Ti a and/3 subunits from clones of differing specificities demonstrated that clonally unique peptides as well as shared peptides existed in each subunit, thus implying that variable (V) as well as constant (C) domains existed within Ti and/3 molecules (5, 9). Subsequently, N-terminal amino acid sequencing and molecular cloning techniques led to identification of the Ti /3 gene structure, and showed that specific V-, D(diversity), J(joining), and C-like segments fuse to form an active/3 gene (10-16). These studies al...
Proceedings of the National Academy of Sciences
Proc. Natl. Acad. Sci. USA Vol. 83, pp. 9679-9683, December 1986 Immunology ... JACQUES VAN SNICK... more Proc. Natl. Acad. Sci. USA Vol. 83, pp. 9679-9683, December 1986 Immunology ... JACQUES VAN SNICK*, SYLVIE CAYPHASt, ANNE VINKt, CATHERINE UYTTENHOVE*, PIERRE G. COULIEt, ... MICHAEL R. RUBIRAt, AND RICHARD J. SIMPSON: *Ludwig ...
Der Onkologe
Regulation des Zellzyklus und therapeutische Implikationen induzieren die Zellzyklusprogression u... more Regulation des Zellzyklus und therapeutische Implikationen induzieren die Zellzyklusprogression und sind somit ein wichtiges Element der Zellzyklusregulation.
Hodgkin’s disease is histopathologically characterized by the relative scarcity of neoplastic Hod... more Hodgkin’s disease is histopathologically characterized by the relative scarcity of neoplastic Hodgkin and Reed-Sternberg cells and for yet unknown reasons by an abundant reactive background of T lymphocytes and often eosinophils. Eotaxin is a CC-chemokine attracting eosinophils and T helper 2 (Th2) cells in allergic inflammation. We now report that eotaxin is strongly expressed in fibroblasts of Hodgkin’s disease tissues, whereas Hodgkin/Reed-Sternberg cells do not express this chemokine. In tissue culture, Hodgkin’s disease tumor cells induce eotaxin expression in cocultured dermal fibroblasts in a concentration leading to a specific chemotactic response of a Th2 cell clone. Production of tumor necrosis factor-a (TNF-a) by Hodgkin/Reed-Sternberg cells appears to be responsible for this induction, because blocking of TNF-a by neutralizing antibodies prevented
Journal of Clinical Oncology, 2007
563 Background: Y-box binding protein (YB-1), known as oncogenic transcription factor, is associa... more 563 Background: Y-box binding protein (YB-1), known as oncogenic transcription factor, is associated with up-regulation of MDR1, alters p53 function, and induces growth of an aggressive phenotype. In high-risk breast cancer, the prospective randomized WSG-AM-01 trial has reported significantly better event-free (EFS) and overall survival (OS) for tandem high-dose (HD) vs. dose-dense (DD) chemotherapy, especially in basal-like und HER2 subgroups. The present study examines the interaction of a drug resistant phenotype induced by YB-1 within the WSG-AM-01 collective at 5-year follow-up. Methods: 236 tumors (116 HD/120 DD) of 403 randomized patients (60%) were available for construction of tissue microarrays and determination of molecular classification by k-clustering of expression of 34 protein markers. Immunostaining of YB-1 by specific peptide antibody was scored semiquatitatively by intensity. Associations of YB-1 staining with other protein expression factors were studied by Pear...
Zeitschrift für Naturforschung C, 1978
Hepatitis A-Yirus-Single-Sranded D N A , Electron Microscopy, Length Measurements, Parvovirus Hep... more Hepatitis A-Yirus-Single-Sranded D N A , Electron Microscopy, Length Measurements, Parvovirus Hepatitis A-virus was purified from human stools by three purification steps. Virus was identified by radioimmuno-assay and purity monitored with immune electron microscopy. Virus particles, serologically and morphologically identical, banded in CsCl in two density ranges at 1.31 — 1.34 g/cm3 and at 1.41 — 1.43 g/cm3. Virions of density 1.31 — 1.34 g/cm3 were shown to contain single-stranded D N A of different size classes. Class I 1.33 kb, class I I 4.61 kb in addition a small amount of molecules was de tected with lengths up to 15 kb.
The Biology of Idiotypes, 1984
In his original proposal of an immunoregulatory network of lymphocytes, Jerne proposed that the n... more In his original proposal of an immunoregulatory network of lymphocytes, Jerne proposed that the naive immune system is in a negatively regulated state.(1) Before the introduction of antigen, a lymphocyte specific for a certain antigenic determinant (epitope) is held in check by another lymphocyte’s anti-idiotypic receptor. In this network all antibodies represent anti-idiotypes. The appearance of antigen perturbs this homeostatic down-regulation and an immune response is generated. As a consequence of the immune response to the individual epitopes, the amount of antigen is reduced below a threshold level whereupon the systems returns to homeostasis. In recent years, the mechanism by which the immune response is regulated has been investigated. Antigen-specific(2) and nonspecific(3) T-suppressor (Ts) cells play a critical role in this regulation. Further, idiotype-anti-idiotype interactions may be important in both Ts—target cell and Ts—Ts interactions. However, rather than existing in a down-regulated state before the appearance of an antigen, the immune system can be thought of as a complex set of dynamically activated and regulated cellular elements. Antigen stimulates an immune response (postive) and then initiates immunoregulatory (negative) events, instead of simply perturbing homeostatic regulation. Differential antigen presentation to T-helper (Th) and Ts cells by specific antigen-presenting cells (APCs) may shift this delicate balance from immunity to immune regulation. It appears that presentation of antigen by an I-A+ I-J− APC activates Th(4) cells, while an I-J+ I-A− APC activates Ts cells.(5) Moreover, differential expression of I-A- or I-J- encoded molecules on APCs might mediate these processes. On the other hand, T-cell idiotypes may serve as cell interaction molecules in immunoregulatory events subsequent to Ts activation.(6)
Journal of Pharmacology and Experimental Therapeutics, 2009
NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)carbonylimino)... more NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)carbonylimino))-bis(1,3-xylene-α,α'-diphosphonic acid) tetrasodium salt] is a nonnucleotide P2Y 11 agonist and stimulates release of IL-8 from human monocyte-derived dendritic cells
Journal of Experimental Medicine, 1985
The chromosomal location of Ti alpha was determined by hybridization of a radiolabeled cDNA for t... more The chromosomal location of Ti alpha was determined by hybridization of a radiolabeled cDNA for the alpha chain of human T cell receptor with 12 human X mouse cell hybrid DNAs cleaved with BamHI. Seven hybrids contained human Ti alpha, while the remaining five lacked it. Only human chromosome 14 matched the distribution of human Ti alpha signal across the mapping panel. Hybrids segregating a chromosome 14 translocation were used to demonstrate that Ti alpha is in the region 14pter greater than 14q21. Thus, the alpha and beta chain genes that contribute structural components to the Ti moiety of the human T cell receptor lie on different chromosomes. In humans, the immunoglobulin heavy chain locus and Ti alpha are in different regions of chromosome 14, with Ti alpha more proximal and the immunoglobulin heavy chain locus more distal.
Cancer Research, 2010
Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >... more Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >40% of breast cancers, where it is associated with poor prognosis, disease recurrence, and drug resistance. We questioned whether this may be linked to the ability of YB-1 to induce the expression of genes linked to cancer stem cells such as CD44 and CD49f. Herein, we report that YB-1 binds the CD44 and CD49f promoters to transcriptionally upregulate their expressions. The introduction of wild-type (WT) YB-1 or activated P-YB-1S102 stimulated the production of CD44 and CD49f in MDA-MB-231 and SUM 149 breast cancer cell lines. YB-1–transfected cells also bound to the CD44 ligand hyaluronan more than the control cells. Similarly, YB-1 was induced in immortalized breast epithelial cells and upregulated CD44. Conversely, silencing YB-1 decreased CD44 expression as well as reporter activity in SUM 149 cells. In mice, expression of YB-1 in the mammary gland induces CD44 and CD49f with associat...
This article cites 55 articles, 19 of which can be accessed free
Current knowledge about molecular mechanisms underlying disease progression and drug resistance i... more Current knowledge about molecular mechanisms underlying disease progression and drug resistance in multiple myeloma (MM) is still limited. Here, we analyzed the potential pathogenetic role of the Y box binding protein YB-1 in MM. YB-1 is a member of the cold shock domain protein superfamily and involved in various cellular functions like proliferation. Immunohistochemical analyses revealed that neither normal bone marrow (BM) plasma cells (PCs), premalignant PCs of patients with monoclonal gammopathy of unknown significance (MGUS) nor MM cells with a mature morphology showed expression of YB-1 in situ . In contrast, YB-1 was strongly expressed in situ in normal PC precursor blasts as well as in a MM subset and in vitro in all of the evaluated MM cell lines. The YB-1 expressing MM cells were characterized by an immature morphology and a highly proliferative phenotype as defined by Ki 67 expression. We observed that siRNA-mediated knockdown of YB-1 decreased proliferation and induced ...
Biochemical Pharmacology, 2015
Tinzaparin overcomes the proteoglycan-mediated cisplatin resistance in A2780cis cells by a transc... more Tinzaparin overcomes the proteoglycan-mediated cisplatin resistance in A2780cis cells by a transcriptional reprogramming, thus supporting cisplatin induced apoptosis.
Journal of Biological Chemistry, 2003
The multifunctional DNA-and RNA-associated Y-box protein 1 (YB-1) specifically binds to splicing ... more The multifunctional DNA-and RNA-associated Y-box protein 1 (YB-1) specifically binds to splicing recognition motifs and regulates alternative splice site selection. Here, we identify the arginine/serine-rich SRp30c protein as an interacting protein of YB-1 by performing a two-hybrid screen against a human mesangial cell cDNA library. Co-immunoprecipitation studies confirm a direct interaction of tagged proteins YB-1 and SRp30c in the absence of RNA via two independent protein domains of YB-1. A high affinity interaction is conferred through the N-terminal region. We show that the subcellular YB-1 localization is dependent on the cellular SRp30c content. In proliferating cells, YB-1 localizes to the cytoplasm, whereas FLAG-SRp30c protein is detected in the nucleus. After overexpression of YB-1 and FLAG-SRp30c, both proteins are co-localized in the nucleus, and this requires the N-terminal region of YB-1. Heat shock treatment of cells, a condition under which SRp30c accumulates in stress-induced Sam68 nuclear bodies, abrogates the co-localization and YB-1 shuttles back to the cytoplasm. Finally, the functional relevance of the YB-1/SRp30c interaction for in vivo splicing is demonstrated in the E1A minigene model system. Here, changes in splice site selection are detected, that is, overexpression of YB-1 is accompanied by preferential 5 splicing site selection and formation of the 12 S isoform.
Journal of Biological Chemistry, 2003
Expression of the Y-box protein YB-1 is increased in proliferating normal and cancer cells, but i... more Expression of the Y-box protein YB-1 is increased in proliferating normal and cancer cells, but its role in cell proliferation and cell cycle progression is unclear. We have identified a cell cycle-dependent relocalization of YB-1 from the cytoplasm to the nucleus at the G 1 /S phase transition and demonstrate that both the charged zipper and the cold shock domain are involved in regulating this process. Using cell lines that constitutively overexpress YB-1, we show that nuclear accumulation of YB-1 is associated with increased cyclin A and cyclin B1 mRNA and protein expression. We provide evidence that deregulated YB-1 expression is linked to adhesion-independent cell proliferation through the induction of cyclin A. Thus, we have identified YB-1 as a cell cycle stage-specific transcription factor important for cell proliferation. Y-box proteins belong to a family of evolutionary conserved proteins, which function as transcription factors, regulators of RNA metabolism, and protein synthesis (reviewed in Refs. 1 and 2). Y-box proteins might play important developmental roles in early embryogenesis (3). In non-dividing germ cells, Y-box proteins regulate the utilization of maternal and paternal stores of mRNA by the translational machinery (4-7). YB-1 was first identified as a DNA-binding protein that interacts with the Y-box sequence in major histocompatibility complex class II promoters (8). High levels of YB-1 are present in human fetal tissues of the heart, muscle, liver, lung, adrenal gland, and the brain (9). In contrast, the YB-1 expression patterns in most adult human tissues are unknown. A role of Y-box proteins in regulation of cell proliferation has been discussed, and high expression of Y-box proteins occurs under conditions of cell proliferation, e.g. in certain embryonal tissues, in fetal liver, in the regenerating liver after tissue damage (10), and in the proliferating compartment of colorectal mucosa (11). YB-1
Cancer Research, 2009
Platinum plays a central role in the therapy of ovarian cancer, and the emergence of platinum res... more Platinum plays a central role in the therapy of ovarian cancer, and the emergence of platinum resistance is a major obstacle for clinical management of the disease. We treated A2780 ovarian cancer cells by weekly cycles of cisplatin over a period of 6 months and unveiled that enhanced insulin-like growth factor I receptor (IGF-IR) expression and autocrine IGF-I are associated with hyperactivation of the IGF-IR and phosphatidylinositol-3-OH kinase (PI3K) pathways in cisplatin-resistant cells. IGF-IR expression levels increased during treatment cycles and correlated with cisplatin resistance. Purified IGF-I induced cisplatin resistance in diverse ovarian cancer cell lines, and small molecule inhibitors proved that IGF-IR and PI3K are essential for cisplatin resistance. Similar results were obtained with BG-1 ovarian cancer cells. Cytogenetic and array comparative genomic hybridization analyses revealed selection and de novo formation of chromosomal alterations during resistance develo...
Human Molecular Genetics, 2014
The WT1 gene encodes a zinc finger transcription factor important for normal kidney development. ... more The WT1 gene encodes a zinc finger transcription factor important for normal kidney development. WT1 is a suppressor for Wilms tumour development and an oncogene for diverse malignant tumours. We recently established cell lines from primary Wilms tumours with different WT1 mutations. To investigate the function of mutant WT1 proteins, we performed WT1 knockdown experiments in cell lines with a frameshift/extension (p.V432fsX87 5 Wilms3) and a stop mutation (p.P362X 5 Wilms2) of WT1, followed by genome-wide gene expression analysis. We also expressed wild-type and mutant WT1 proteins in human mesenchymal stem cells and established gene expression profiles. A detailed analysis of gene expression data enabled us to classify the WT1 mutations as gain-of-function mutations. The mutant WT1 Wilms2 and WT1 Wilms3 proteins acquired an ability to modulate the expression of a highly significant number of genes from the G2/M phase of the cell cycle, and WT1 knockdown experiments showed that they are required for Wilms tumour cell proliferation. p53 negatively regulates the activity of a large number of these genes that are also part of a core proliferation cluster in diverse human cancers. Our data strongly suggest that mutant WT1 proteins facilitate expression of these cell cycle genes by antagonizing transcriptional repression mediated by p53. We show that mutant WT1 can physically interact with p53. Together the findings show for the first time that mutant WT1 proteins have a gain-of-function and act as oncogenes for Wilms tumour development by regulating Wilms tumour cell proliferation.
Human Molecular Genetics, 2010
Wilms tumors (WTs) are genetically heterogeneous kidney tumors whose cells of origin are unknown.... more Wilms tumors (WTs) are genetically heterogeneous kidney tumors whose cells of origin are unknown. Tumors with WT1 mutations and concomitant loss of the wild-type allele represent a distinct subgroup, frequently associated with mutations in CTNNB1. Here, we describe the establishment and characterization of long-term cell cultures derived from five individual WTs with WT1 mutations. Three of these tumor cell lines also had CTNNB1 mutations and an activated canonical Wnt signaling pathway as measured by b-catenin/ T cell-specific transcription factor (TCF) transcriptional activity. Four of the five Wilms cell lines had a stable normal karyotype for at least 25 passages, and four lines showed loss of heterozygosity of chromosome 11p due to mitotic recombination in 11p11. Gene expression profiling revealed that the WT cell lines are highly similar to human mesenchymal stem cells (MSCs) and FACS analysis demonstrated the expression of MSCspecific surface proteins CD105, CD90 and CD73. The stem cell like nature of the WT cells is further supported by their adipogenic, chondrogenic, osteogenic and myogenic differentiation potentials. By generating multipotent mesenchymal precursors from paraxial mesoderm (PAM) in tissue culture using embryonal stem cells, gene expression profiles of PAM and MSCs were described. Using these published gene sets, we found coexpression of a large number of genes in WT cell lines, PAM and MSCs. Lineage plasticity is indicated by the simultaneous expression of genes from the mesendodermal and neuroectodermal lineages. We conclude that WTs with WT1 mutations have specific traits of PAM, which is the source of kidney stromal cells.
Journal of Biological Chemistry, 2006
Journal of Biological Chemistry, 2007
The use of platinum complexes for the therapy of breast cancer is an emerging new treatment modal... more The use of platinum complexes for the therapy of breast cancer is an emerging new treatment modality. To gain insight into the mechanisms underlying cisplatin resistance in breast cancer, we used estrogen receptor-positive MCF-7 cells as a model system. We generated cisplatin-resistant MCF-7 cells and determined the functional status of epidermal growth factor receptor (EGFR), MAPK, and AKT signaling pathways by phosphoreceptor tyrosine kinase and phospho-MAPK arrays. The cisplatinresistant MCF-7 cells are characterized by increased EGFR phosphorylation, high levels of AKT1 kinase activity, and ERK1 phosphorylation. In contrast, the JNK and p38 MAPK modules of the MAPK signaling pathway were inactive. These conditions were associated with inactivation of the p53 pathway and increased BCL-2 expression. We investigated the expression of genes encoding the ligands for the ERBB signaling cascade and found a selective up-regulation of amphiregulin expression, which occurred at later stages of cisplatin resistance development. Amphiregulin is a specific ligand of the EGFR (ERBB1) and a potent mitogen for epithelial cells. After exposure to cisplatin, the resistant MCF-7 cells secreted amphiregulin protein over extended periods of time, and knockdown of amphiregulin expression by specific short interfering RNA resulted in a nearly complete reversion of the resistant phenotype. To demonstrate the generality and importance of our findings, we examined amphiregulin expression and cisplatin resistance in a variety of human breast cancer cell lines and found a highly significant correlation. In contrast, amphiregulin levels did not significantly correlate with cisplatin resistance in a panel of lung cancer cell lines. We have thus identified a novel function of amphiregulin for cisplatin resistance in human breast cancer cells.
T cell receptors for antigen and major histocompatibility complex (MHC) ~ determinants have, usin... more T cell receptors for antigen and major histocompatibility complex (MHC) ~ determinants have, using anticlonotypic monoclonal antibodies (mAb), been defined on inducer, suppressor, and class I and class II MHC-specific cytotoxic T lymphocytes as T3oassociated molecules of 90 kilodaltons (kD) molecular mass (1-8). These cionotypic structures, termed Ti, are comprised of one 49-54 kD a and one 43 kD/3 subunit, which are disulfide linked. Peptide mapping analysis of isolated Ti a and/3 subunits from clones of differing specificities demonstrated that clonally unique peptides as well as shared peptides existed in each subunit, thus implying that variable (V) as well as constant (C) domains existed within Ti and/3 molecules (5, 9). Subsequently, N-terminal amino acid sequencing and molecular cloning techniques led to identification of the Ti /3 gene structure, and showed that specific V-, D(diversity), J(joining), and C-like segments fuse to form an active/3 gene (10-16). These studies al...
Proceedings of the National Academy of Sciences
Proc. Natl. Acad. Sci. USA Vol. 83, pp. 9679-9683, December 1986 Immunology ... JACQUES VAN SNICK... more Proc. Natl. Acad. Sci. USA Vol. 83, pp. 9679-9683, December 1986 Immunology ... JACQUES VAN SNICK*, SYLVIE CAYPHASt, ANNE VINKt, CATHERINE UYTTENHOVE*, PIERRE G. COULIEt, ... MICHAEL R. RUBIRAt, AND RICHARD J. SIMPSON: *Ludwig ...
Der Onkologe
Regulation des Zellzyklus und therapeutische Implikationen induzieren die Zellzyklusprogression u... more Regulation des Zellzyklus und therapeutische Implikationen induzieren die Zellzyklusprogression und sind somit ein wichtiges Element der Zellzyklusregulation.