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Berlin Brandenburg

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  • 1
    Language: English
    In: Nature reviews. Cancer, March 2007, Vol.7(3), pp.165-8
    Description: The role of p53 as a tumour suppressor is generally attributed to its ability to stop the proliferation of precancerous cells by inducing cell-cycle arrest or apoptosis. The relatives and evolutionary predecessors of p53 - p63 and p73 - share the tumour-suppressor activity of p53 to some extent, but also have essential functions in embryonic development and differentiation control. Recent evidence indicates that these ancestral functions in differentiation control contribute to the tumour-suppressor activity that the p53 family is famous for.
    Keywords: Cell Differentiation -- Physiology ; Cell Transformation, Neoplastic -- Metabolism ; Genes, P53 -- Physiology
    ISSN: 1474-175X
    E-ISSN: 14741768
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  • 2
    In: PLoS ONE, 2015, Vol.10(4)
    Description: RAS mutations are frequently found among acute myeloid leukemia patients (AML), generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We have previously shown that treatment of AML patients with high-dose cytarabine is preferentially beneficial for those harboring oncogenic RAS. On the basis of a murine AML cell culture model, we ascribed this effect to a RAS-driven, p53-dependent induction of differentiation. Hence, in this study we sought to confirm the correlation between RAS status and differentiation of primary blasts obtained from AML patients. The gene expression signature of AML blasts with oncogenic NRAS indeed corresponded to a more mature profile compared to blasts with wildtype RAS , as demonstrated by gene set enrichment analysis (GSEA) and real-time PCR analysis of myeloid ecotropic viral integration site 1 homolog ( MEIS1 ) in a unique cohort of AML patients. In addition, in vitro cell culture experiments with established cell lines and a second set of primary AML cells showed that oncogenic NRAS mutations predisposed cells to cytarabine (AraC) driven differentiation. Taken together, our findings show that AML with inv(16) and NRAS mutation have a differentiation gene signature, supporting the notion that NRAS mutation may predispose leukemic cells to AraC induced differentiation. We therefore suggest that promotion of differentiation pathways by specific genetic alterations could explain the superior treatment outcome after therapy in some AML patient subgroups. Whether a differentiation gene expression status may generally predict for a superior treatment outcome in AML needs to be addressed in future studies.
    Keywords: Research Article
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(9), p.e0139073
    Description: Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3+), cytotoxic-T cells (CD8+), T-helper cells (CD4+), B cells (CD20+), macrophages (CD68+), mast cells (CD117+), mononuclear cells (CD11c+), plasma cells, activated-T cells (MUM1+), B cells, myeloid cells (PD1+) and neutrophilic granulocytes (myeloperoxidase+) compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1+ cells) in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: The Journal of biological chemistry, 14 December 2018, Vol.293(50), pp.19250-19262
    Description: Different transcription factors operate together at promoters and enhancers to regulate gene expression. Transcription factors either bind directly to their target DNA or are tethered to it by other proteins. The transcription factor Sp2 serves as a paradigm for indirect genomic binding. It does not require its DNA-binding domain for genomic DNA binding and occupies target promoters independently of whether they contain a cognate DNA-binding motif. Hence, Sp2 is strikingly different from its closely related paralogs Sp1 and Sp3, but how Sp2 recognizes its targets is unknown. Here, we sought to gain more detailed insights into the genomic targeting mechanism of Sp2. ChIP-exo sequencing in mouse embryonic fibroblasts revealed genomic binding of Sp2 to a composite motif where a recognition sequence for TALE homeoproteins and a recognition sequence for the trimeric histone-fold domain protein nuclear transcription factor Y (Nf-y) are separated by 11 bp. We identified a complex consisting of the TALE homeobox protein Prep1, its partner PBX homeobox 1 (Pbx1), and Nf-y as the major partners in Sp2-promoter interactions. We found that the Pbx1:Prep1 complex together with Nf-y recruits Sp2 to co-occupied regulatory elements. In turn, Sp2 potentiates binding of Pbx1:Prep1 and Nf-y. We also found that the Sp-box, a short sequence motif close to the Sp2 N terminus, is crucial for Sp2's cofactor function. Our findings reveal a mechanism by which the DNA binding-independent activity of Sp2 potentiates genomic loading of Pbx1:Prep1 and Nf-y to composite motifs present in many promoters of highly expressed genes.
    Keywords: Pbx1 ; Prep1 ; Tale Homeoproteins ; Chromatin Immunoprecipitation (Chip) ; Gene Regulation ; Nuclear Factor Y (Nf-Y) ; Specificity Protein 1 (Sp1) ; Transcription Factor ; Transcription Factor Sp2 ; Transcription Target Gene
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 5
    Language: English
    In: Drug Resistance Updates, May 2018, Vol.38, pp.27-43
    Description: The tumor suppressive transcription factor p53 regulates a wide array of cellular processes that confer upon cells an essential protection against cancer development. Wild-type p53 regulates gene expression by directly binding to DNA in a sequence-specific manner. p53 missense mutations are the most common mutations in malignant cells and can be regarded as synonymous with anticancer drug resistance and poor prognosis. The current review provides an overview of how the extraordinary variety of more than 2000 different mutant p53 proteins, known as the p53 mutome, affect the interaction of p53 with DNA. We discuss how the classification of p53 mutations to loss of function (LOF), gain of function (GOF), and dominant-negative (DN) inhibition of a remaining wild-type allele, hides a complex p53 mutation spectrum that depends on the distinctive nature of each mutant protein, requiring different therapeutic strategies for each mutant p53 protein. We propose to regard the different mutant p53 categories as continuous variables, that may not be independent of each other. In particular, we suggest here to consider GOF mutations as a special subset of LOF mutations, especially when mutant p53 binds to DNA through cooperation with other transcription factors, and we present a model for GOF mechanism that consolidates many observations on the GOF phenomenon. We review how novel mutant p53 targeting approaches aim to restore a wild-type-like DNA interaction and to overcome resistance to cancer therapy.
    Keywords: P53 ; Tumor Suppressor ; DNA Binding ; Targeted Therapy ; Drug Resistance ; Biology
    ISSN: 1368-7646
    E-ISSN: 1532-2084
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  • 6
    Language: English
    In: The Journal of neuroscience : the official journal of the Society for Neuroscience, 24 January 2018, Vol.38(4), pp.858-877
    Description: Schwann cell differentiation and myelination depends on chromatin remodeling, histone acetylation, and methylation, which all affect Schwann cell proliferation. We previously reported that the deletion of the POZ (POxvirus and Zinc finger) domain of the transcription factor Miz1 (Myc-interacting zinc finger protein; encoded by ) in mouse Schwann cells (Δ) causes a neuropathy at 90 d after birth [postnatal day (P) 90], with a subsequent spontaneous regeneration. Here we show that RNA sequencing from Δ and control animals at P30 revealed a set of upregulated genes with a strong correlation to cell-cycle regulation. Consistently, a subset of Schwann cells did not exit the cell cycle as observed in control animals and the growth fraction increased over time. From the RNAseq gene list, two direct Miz1 target genes were identified, one of which encodes the histone H3K36 demethylase Kdm8. We show that the expression of is repressed by Miz1 and that its release in Δ cells induces a decrease of H3K36, especially in deregulated cell-cycle-related genes. The linkage between elevated expression, hypomethylation of H3K36 at cell-cycle-relevant genes, and the subsequent re-entering of adult Schwann cells into the cell cycle suggests that the release of repression in the absence of a functional Miz1 is a central issue in the development of the Δ phenotype. The deletion of the Miz1 (Myc-interacting zinc finger protein 1) POZ (POxvirus and Zinc finger) domain in Schwann cells causes a neuropathy. Here we report sustained Schwann cell proliferation caused by an increased expression of the direct Miz1 target gene , encoding a H3K36me2 demethylase. Hence, the demethylation of H3K36 is linked to the pathogenesis of a neuropathy.
    Keywords: Kdm8 ; Miz1 ; Schwann Cell ; Histone Demethylation ; Peripheral Neuropathy ; Proliferation ; Demyelinating Diseases -- Metabolism ; Jumonji Domain-Containing Histone Demethylases -- Metabolism ; Nuclear Proteins -- Metabolism ; Peripheral Nervous System Diseases -- Metabolism ; Protein Inhibitors of Activated Stat -- Metabolism ; Schwann Cells -- Metabolism
    ISSN: 02706474
    E-ISSN: 1529-2401
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  • 7
    Language: English
    In: Nucleic acids research, 20 April 2018, Vol.46(7), pp.3412-3428
    Description: SKI is a transcriptional co-regulator and overexpressed in various human tumors, for example in acute myeloid leukemia (AML). SKI contributes to the origin and maintenance of the leukemic phenotype. Here, we use ChIP-seq and RNA-seq analysis to identify the epigenetic alterations induced by SKI overexpression in AML cells. We show that approximately two thirds of differentially expressed genes are up-regulated upon SKI deletion, of which 〉40% harbor SKI binding sites in their proximity, primarily in enhancer regions. Gene ontology analysis reveals that many of the differentially expressed genes are annotated to hematopoietic cell differentiation and inflammatory response, corroborating our finding that SKI contributes to a myeloid differentiation block in HL60 cells. We find that SKI peaks are enriched for RUNX1 consensus motifs, particularly in up-regulated SKI targets upon SKI deletion. RUNX1 ChIP-seq displays that nearly 70% of RUNX1 binding sites overlap with SKI peaks, mainly at enhancer regions. SKI and RUNX1 occupy the same genomic sites and cooperate in gene silencing. Our work demonstrates for the first time the predominant co-repressive function of SKI in AML cells on a genome-wide scale and uncovers the transcription factor RUNX1 as an important mediator of SKI-dependent transcriptional repression.
    Keywords: Core Binding Factor Alpha 2 Subunit -- Genetics ; Leukemia, Myeloid, Acute -- Genetics ; Regulatory Elements, Transcriptional -- Genetics
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 8
    Language: English
    In: Cell Cycle, 03 April 2017, Vol.16(7), pp.591-592
    Keywords: Calnexin ; Calreticulin ; Entpd5 ; Mutant P53 ; N-Glycosylation ; Protein Folding ; Biology
    ISSN: 1538-4101
    E-ISSN: 1551-4005
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  • 9
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 19 September 2017, Vol.114(38), pp.E8035-E8044
    Description: Casein kinase 1α (CK1α), a component of the β-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1α (encoded by ) in skin physiology, we crossed mice harboring floxed with mice expressing K14-Cre-ER to generate mice in which tamoxifen induces the deletion of exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1α loss was accompanied by β-catenin and p53 stabilization, with the preferential induction of p53 target genes, but phenotypically most striking was hyperpigmentation of the skin, importantly without tumorigenesis, for at least 9 mo after ablation. The number of epidermal melanocytes and eumelanin levels were dramatically increased in SKO mice. To clarify the putative role of p53 in epidermal hyperpigmentation, we established K14-Cre-ER CK1α/p53 double-knockout (DKO) mice and found that coablation failed to induce epidermal hyperpigmentation, demonstrating that it was p53-dependent. Transcriptome analysis of the epidermis revealed p53-dependent up-regulation of Kit ligand (KitL). SKO mice treated with ACK2 (a Kit-neutralizing antibody) or imatinib (a Kit inhibitor) abrogated the CK1α ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of α-melanocyte-stimulating hormone (α-MSH), was not activated in the CK1α ablation-induced hyperpigmentation, which is in contrast to the mechanism of p53-dependent UV tanning. Nevertheless, acute sunburn effects were successfully prevented in the hyperpigmented skin of SKO mice. CK1α inhibition induces skin-protective eumelanin but no carcinogenic pheomelanin and may therefore constitute an effective strategy for safely increasing eumelanin via UV-independent pathways, protecting against acute sunburn.
    Keywords: Kit Ligand ; Casein Kinase 1α ; Melanocyte ; P53 ; Sunburn ; Skin Pigmentation ; Casein Kinase I -- Metabolism ; Keratinocytes -- Metabolism ; Sunburn -- Metabolism ; Tumor Suppressor Protein P53 -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 27 December 2016, Vol.113(52), pp.E8433-E8442
    Description: Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5'-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.
    Keywords: Entpd5 ; N-Glycosylation ; Metastasis ; P53 ; Tumor Suppressor ; Neoplasm Metastasis ; Endoplasmic Reticulum -- Metabolism ; Oncogene Proteins -- Metabolism ; Pyrophosphatases -- Metabolism ; Tumor Suppressor Protein P53 -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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