Kooperativer Bibliotheksverbund

Berlin Brandenburg

and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Type of Medium
Language
Year
  • 1
    Language: English
    In: Cancer research, 01 June 2017, Vol.77(11), pp.3040-3056
    Description: Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic deletion in mouse models of -mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, -deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, -deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling mutations, particularly given their impact on PARP1 and ATR inhibitors. .
    Keywords: Adenocarcinoma -- Drug Therapy ; Ataxia Telangiectasia Mutated Proteins -- Metabolism ; Lung Neoplasms -- Drug Therapy ; Poly(Adp-Ribose) Polymerase Inhibitors -- Therapeutic Use
    ISSN: 00085472
    E-ISSN: 1538-7445
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(5), p.e0125745
    Description: Growing evidence suggests a key role for RNA binding proteins (RBPs) in genome stability programs. Additionally, recent developments in RNA sequencing technologies, as well as mass-spectrometry techniques, have greatly expanded our knowledge on protein-RNA interactions. We here use full transcriptome sequencing and label-free LC/MS/MS to identify global changes in protein-RNA interactions in response to etoposide-induced genotoxic stress. We show that RBPs have distinct binding patterns in response to genotoxic stress and that inactivation of the RBP regulator module, p38/MK2, can affect the entire spectrum of protein-RNA interactions that take place in response to stress. In addition to validating the role of known RBPs like Srsf1, Srsf2, Elavl1 in the genotoxic stress response, we add a new collection of RBPs to the DNA damage response. We identify Khsrp as a highly regulated RBP in response to genotoxic stress and further validate its role as a driver of the G(1/)S transition through the suppression of Cdkn1a(P21) transcripts. Finally, we identify KHSRP as an indicator of overall survival, as well as disease free survival in glioblastoma multiforme.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    Language: English
    In: BBA - Molecular Basis of Disease, 2011, Vol.1812(5), pp.573-580
    Description: Hyperglycemia in patients with type 2 diabetes causes multiple neuronal complications, e.g., diabetic polyneuropathy, cognitive decline, and embryonic neural crest defects due to increased apoptosis. Possible mechanisms of neuronal response to increased glucose burden are still a matter of debate. Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. The insulin receptor substrates (IRS) are intracellular adapter proteins mediating insulin's and IGF-1's intracellular effects. Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. However, MAP-kinases inhibition had only minor impact. IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1. ► Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. ► IRS-1/-2 overexpression induces resistance to glucose-induced caspase-3 activation. ► Inhibition of PI3-kinase reverses the protective effect of IRS-1/-2. ► FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. ► IRS-1/-2 regulates neuronal MnSOD expression.
    Keywords: Glucose ; Apoptosis ; Insulin Receptor Substrate ; Mnsod ; Neuron ; Biology ; Chemistry
    ISSN: 0925-4439
    E-ISSN: 1879-260X
    E-ISSN: 18782434
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    Language: English
    In: The Journal of endocrinology, February 2010, Vol.204(2), pp.199-208
    Description: Since neuronal insulin receptor substrate 2 (IRS2)-mediated signals coordinate key processes in rodent physiology such as food intake, fertility, longevity, and aging-related behavior, we analyzed the mechanisms of neuronal IRS2 expression in neuroblastoma (SHSY5Y) and hypothalamic (GT1-7) cell lines. Using dual luciferase reporter assays and IRS2 promoter deletion constructs, we identified a regulatory cassette within the IRS2 promoter between -779 and -679 bp from the translational start which is responsible for approximately 50% of neuronal IRS2 promoter activity. Chromatin immunoprecipitation assays and electromobility shift assay revealed four overlapping ZBP89/specificity protein 1 (SP1) binding sites which alternatively bind to ZBP89 (ZNF148 as listed in the HUGO Database) or SP1. Activation of this cassette is inhibited by phosphoinositide-3-kinase (PI3K) via increased ZBP89 binding to the promoter. Serum starvation caused increased SP1 binding at one specific SP1 site and decreased binding to another, proving a regulatory interaction between the different binding sites within this promoter cassette to tightly control IRS2 expression. Mutants containing all the possible combinations of one, two, three, or all the four SP1 binding sites of the IRS2 promoter revealed that SP1 binding to one particular site is most important for promoter activation. Stable downregulation of ZBP89 using siRNA substantially increased IRS2 mRNA and protein expression. Thus, alternative binding of ZBP89 or SP1 to the described region in the IRS2 promoter regulates neuronal IRS2 expression in a PI3K-dependent manner.
    Keywords: Gene Expression Regulation ; DNA-Binding Proteins -- Metabolism ; Insulin Receptor Substrate Proteins -- Metabolism ; Neurons -- Metabolism ; Sp1 Transcription Factor -- Metabolism ; Transcription Factors -- Metabolism
    ISSN: 00220795
    E-ISSN: 1479-6805
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    Language: English
    In: Cancer discovery, May 2014, Vol.4(5), pp.592-605
    Description: Here, we use a large-scale cell line-based approach to identify cancer cell-specific mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profiled the mutational landscape across 1,319 cancer-associated genes of 67 distinct cell lines and identified numerous genes involved in homologous recombination-mediated DNA repair, including BRCA1, BRCA2, ATM, PAXIP, and RAD50, as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3, which have been reported to occur recurrently in numerous human cancer entities, emerged as the most significant predictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3-mutant cell lines in vitro and displayed remarkable single-agent efficacy against MSH3-mutant tumors in vivo. Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects.
    Keywords: Colonic Neoplasms -- Drug Therapy ; DNA-Activated Protein Kinase -- Antagonists & Inhibitors ; DNA-Binding Proteins -- Genetics ; Nuclear Proteins -- Antagonists & Inhibitors
    ISSN: 21598274
    E-ISSN: 2159-8290
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: Diabetes, 2005, Vol.54(12), p.3343(6)
    Description: Cerebral insulin receptors play an important role in regulation of energy homeostasis and development of neurodegeneration. Accordingly, type 2 diabetes characterized by insulin resistance is associated with an increased risk of developing Alzheimer's disease. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases. Here, we directly addressed whether peripheral hyperinsulinemia as one feature of type 2 diabetes can alter in vivo cerebral insulin signaling and tau phosphorylation. Peripheral insulin stimulation rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (PI) 3-kinase pathway activation, and dose-dependent tau phosphorylation at [Ser.sup.202] in the central nervous system. PhosphoFoxO1 and PI-3,4,5-phosphate immunostainings of brains from insulin-stimulated mice showed neuronal staining throughout the brain, not restricted to brain areas without functional blood-brain barrier. Importantly, in insulin-stimulated neuronal/brain-specific insulin receptor knockout mice, cerebral insulin receptor signaling and tau phosphorylation were completely abolished. Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction and site-specific tau phosphorylation in vivo, revealing new insights into the linkage of type 2 diabetes and neurodegeneration.
    Keywords: Metabolic Diseases – Risk Factors ; Metabolic Diseases – Diagnosis ; Metabolic Diseases – Drug Therapy ; Alzheimer&Apos;S Disease – Risk Factors ; Alzheimer&Apos;S Disease – Diagnosis ; Alzheimer&Apos;S Disease – Drug Therapy ; Insulin – Health Aspects
    ISSN: 0012-1797
    E-ISSN: 1939327X
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, October 2009, Vol.23(10), pp.3315-24
    Description: Alzheimer's disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin-like growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF-1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APP(SW), Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-1R (nIGF-1R(-/-)), or neuronal insulin receptor (nIR(-/-)), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS-2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays beta-amyloid (Abeta) accumulation. Analysis of APP metabolism suggested that delayed Abeta accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS-2-mediated disease protection, we analyzed mice with nIGF-1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF-1R(-/-)Tg2576 mice were protected from premature death in the presence of decreased Abeta accumulation specifically in the hippocampus formation. However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD.
    Keywords: Alzheimer Disease -- Metabolism ; Amyloid Beta-Peptides -- Metabolism ; Insulin Receptor Substrate Proteins -- Metabolism ; Insulin-Like Growth Factor I -- Metabolism ; Neurons -- Metabolism ; Receptor, IGF Type 1 -- Metabolism
    ISSN: 08926638
    E-ISSN: 1530-6860
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    In: Journal of Neurochemistry, November 2008, Vol.107(4), pp.907-917
    Description: Insulin‐like growth factor (IGF)‐1 increases proliferation, inhibits apoptosis and promotes differentiation of oligodendrocytes and their precursor cells, indicating an important function for IGF‐1 receptor (IGF‐1R) signaling in myelin development. The insulin receptor substrates (IRS), IRS‐1 and ‐2 serve as intracellular IGF‐1R adaptor proteins and are expressed in neurons, oligodendrocytes and their precursors. To address the role of IRS‐2 in myelination, we analyzed myelination in IRS‐2 deficient (IRS‐2) mice and age‐matched controls during postnatal development. Interestingly, expression of the most abundant myelin proteins, myelin basic protein and proteolipid protein was reduced in IRS‐2 brains at postnatal day 10 (P10) as compared to controls. myelin basic protein immunostaining in P10‐IRS‐2 mice revealed a reduced immunostaining, but an unchanged regional distribution pattern. In cerebral myelin isolates at P10 unaltered relative expression of different myelin proteins was found, indicating quantitatively reduced but not qualitatively altered myelination. Interestingly, up‐regulation of IRS‐1 expression and increased IGF‐1R signaling were observed in IRS‐2 mice at P10‐14, indicating a compensatory mechanism to overcome IRS‐2 deficiency. Adult IRS‐2 mice showed unaltered myelination and motor function. Furthermore, in neuronal/brain‐specific insulin receptor knockout mice myelination was unchanged. Thus, our experiments reveal that IGF‐1R/IRS‐2 mediated signals are critical for appropriate timing of myelination .
    Keywords: Brain ; Insulin Receptor Substrate‐2 ; Insulin‐Like Growth Factor‐1 ; Mice ; Myelin Development
    ISSN: 0022-3042
    E-ISSN: 1471-4159
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    Language: English
    In: Cell Reports, 23 October 2018, Vol.25(4), pp.1027-1039.e6
    Description: , which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a mouse, which harbors an additional allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous -driven lung adenocarcinoma model, we show that mice display a cancer protection phenotype that is indistinguishable from that observed in animals. Moreover, we demonstrate that and cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our allele enabled us to assess the contribution of to -mediated tumor suppression. Torgovnick et al. create a mouse model, carrying a third copy of (p21), which shows enhanced cell-cycle arrest capacity and protection against DNA damage-induced apoptosis. The animals display delayed epithelial regeneration and a robust cancer resistance phenotype, highlighting the importance of p21 in p53-dependent tumor suppression.
    Keywords: Cdkn1a ; P21 ; P53 ; Mouse Model ; Cancer ; Tumor Suppressor ; Cell Cycle Arrest ; Apoptosis ; Cancer Protection ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    Language: English
    In: Journal of Molecular Medicine, 2008, Vol.86(5), pp.597-608
    Description: Generation of new adipocytes plays a major role in the development of obesity. We previously have shown that transcriptional repressor f actor that b inds to I ST (FBI)-1 exerts a dual effect in the process of adipogenesis by inhibiting proliferation and promoting differentiation of preadipocytes. The aim of the present study was to identify FBI-1 regulated molecular effectors that could account for these effects. Overexpressing FBI-1 in preadipocytes resulted in reduced expression of the cell cycle regulator cyclin A, which may explain FBI-1 induced inhibition of proliferation. Interestingly, FBI-1 repressed cyclin A promoter activity through an indirect mechanisms that did not involve direct binding of FBI-1 to the promoter sequence, but rather FBI-1 inhibition of transcriptional activator Sp1 binding to a regulatory element at −452 to −443. We also show that FBI-1 promotes terminal preadipocyte differentiation through a mechanism involving decreased levels of expression of the PPARγ inhibitor E2F-4. FBI-1 significantly reduced E2F-4 promoter activity. Contrary to cyclin A, we found FBI-1-induced repression of E2F-4 is mediated by a direct mechanism via a FBI-1 regulatory element at −11 to −5. As function of transcriptional repressors normally depends on the presence of regulatory co-factors we also performed expression profiling of potential FBI-1 co-repressors throughout adipogenesis. In these experiments Sin3A and histon deacetylase (HDAC)-1 showed a similar expression pattern compared to FBI-1. Strikingly, co-immunoprecipitation studies revealed that FBI-1 binds Sin3A and HDAC-1 to form a repressor complex. Furthermore, by mutational analysis the amino terminal Poxvirus (POZ) domain of FBI-1 was found to be important for Sin3A and HDAC-1 binding. Taken together, FBI-1 is the first transcriptional repressor shown to act as a dual regulator in adipogenesis exerting repressor activities on target genes by both, direct and indirect mechanisms.
    Keywords: Transcriptional repressor ; Dual regulator ; Adipogenesis
    ISSN: 0946-2716
    E-ISSN: 1432-1440
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages