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  • Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines. 17297441

    The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatin-resistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Clock and light regulation of the CREB coactivator CRTC1 in the suprachiasmatic circadian clock. 23699513

    The CREB/CRE transcriptional pathway has been implicated in circadian clock timing and light-evoked clock resetting. To date, much of the work on CREB in circadian physiology has focused on how changes in the phosphorylation state of CREB regulate the timing processes. However, beyond changes in phosphorylation, CREB-dependent transcription can also be regulated by the CREB coactivator CRTC (CREB-regulated transcription coactivator), also known as TORC (transducer of regulated CREB). Here we profiled both the rhythmic and light-evoked regulation of CRTC1 and CRTC2 in the murine suprachiasmatic nucleus (SCN), the locus of the master mammalian clock. Immunohistochemical analysis revealed rhythmic expression of CRTC1 in the SCN. CRTC1 expression was detected throughout the dorsoventral extent of the SCN in the middle of the subjective day, with limited expression during early night, and late night expression levels intermediate between mid-day and early night levels. In contrast to CRTC1, robust expression of CRTC2 was detected during both the subjective day and night. During early and late subjective night, a brief light pulse induced strong nuclear accumulation of CRTC1 in the SCN. In contrast with CRTC1, photic stimulation did not affect the subcellular localization of CRTC2 in the SCN. Additionally, reporter gene profiling and chromatin immunoprecipitation analysis indicated that CRTC1 was associated with CREB in the 5' regulatory region of the period1 gene, and that overexpression of CRTC1 leads to a marked upregulation in period1 transcription. Together, these data raise the prospect that CRTC1 plays a role in fundamental aspects of SCN clock timing and entrainment.
    Document Type:
    Reference
    Product Catalog Number:
    MAB1501
    Product Catalog Name:
    Anti-Actin Antibody, clone C4

  • CLOCK promotes 3T3-L1 cell proliferation via Wnt signaling. 27194636

    Circadian genes control most of the physiological functions including cell cycle. Cell proliferation is a critical factor in the differentiation of progenitor cells. However, the role of Clock gene in the regulation of cell cycle via wingless-type (Wnt) pathway and the relationship between Clock and adipogenesis are unclear. We found that the circadian locomotor output cycles kaput (Clock) regulated the proliferation and the adipogenesis of 3T3-L1 preadipocytes. We found that Clock attenuation inhibited the viability of 3T3-L1 preadipocytes in the cell counting kit 8. The expression of c-Myc and Cyclin D1 decreased dramatically in 3T3-L1 when Clock was silenced with short interfering RNA and was also decreased in fat tissue and adipose tissue-derived stem cells of Clock(Δ19) mice. Clock directly controls the expression of the components of Wnt signal transduction pathway, which was verified by serum shock, chromatin immunoprecipitation, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, IWR-1, a Wnt signal pathway inhibitor, inhibited the cell cycle promotion by CLOCK, which was detected by cell viability assay, flow cytometry, and qRT-PCR. Therefore, CLOCK transcription control of Wnt signaling promotes cell cycle progression in 3T3-L1 preadipocytes. Clock inhibited the adipogenesis on day 2 in 3T3-L1 cells via Oil Red O staining and qRT-PCR detection and probably related to cellular differentiation. These data provide evidence that the circadian gene Clock regulates the proliferation of preadipocytes and affects adipogenesis. © 2016 IUBMB Life, 68(7):557-568, 2016.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™

  • CLOCK interacts with RANBP9 and is involved in alternative splicing in spermatogenesis. 29126923

    The core circadian gene CLOCK plays an important role in regulating male reproduction. However, the underlying mechanism still remains unclear. In the present study, we executed yeast two-hybrid screening using cDNA fragment of CLOCK PAS A domain as bait, and identified RANBP9 as a novel protein interacting with CLOCK. The interaction between CLOCK and RANBP9 was further validated by in vivo and in vitro assays. Previous studies have confirmed that SF3B3 was a RANBP9 interacting protein. Subsequently, our study also found that CLOCK and SF3B3 can interact with each other by co-immunoprecipitation in mouse testis. In order to dissect the underlying mechanism of CLOCK in spermatogenesis, we also performed RNA-immunoprecipitation followed by high-throughput sequencing (RIP-Seq) in mouse testis. The result of sequence analyses and Gene Ontology enrichment analyses (biological processes) demonstrated that CLOCK can directly bind 186 key mRNA transcripts in mouse spermatogenesis. Taken together, our results firstly showed that CLOCK can interact with RANBP9 and bind with mRNAs, demonstrating that CLOCK is involved in alternative splicing in spermatogenesis. These results reveal a novel mechanism for CLOCK in spermatogenesis.
    Document Type:
    Reference
    Product Catalog Number:
    17-700
    Product Catalog Name:
    Magna RIP™ RNA-Binding Protein Immunoprecipitation Kit

  • Circadian clock regulates dynamic chromatin modifications associated with Arabidopsis CCA1/LHY and TOC1 transcriptional rhythms. 23128602

    Circadian clocks enable organisms to adapt to a 24 h diurnal cycle and anticipate rhythmic changes in the environment. The Arabidopsis central oscillator contains three genes encoding core clock components. CIRCADIAN CLOCK ASSOCIATED 1 (CCA1)/LATE ELONGATED HYPOCOTYL (LHY) and TIMING OF CAB EXPRESSION 1 (TOC1) reciprocally repress genes encoding each other and are critical for the generation of circadian rhythms controlling many clock outputs. A precise regulation of transcriptional events is, therefore, essential for proper circadian function. Here, we investigated histone 3 (H3) tail modifications of CCA1, LHY and TOC1 under various conditions. We found specific association of only H3K4Me3 and H3K9/14Ac with the translational start site of these three genes. These H3 marks were enriched at circadian time points of their increased transcription at different photoperiods and under free-running conditions, suggesting circadian regulation of H3 modifications. Analysis of clock-compromised CCA1-overexpressing lines provided evidence that light/dark photoperiods signal the establishment of these chromatin changes which are gated by the clock.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Clock represses preadipocytes adipogenesis via GILZ. 29278648

    Adiposity is a worldwide health threat that needs to be prevented. Circadian gene Clock (circadian locomotor output cycles kaput) is closely correlated to adiposity; for example, weight gain, adipocytes size expansion, and serum lipid level rise in ClockΔ19 mice compared to C57BL/6J mice. However, the precise role of Clock during adipogenic differentiation is unknown. Herein, the circadian gene Clock is shown to regulate adipogenesis mediated by GILZ. Clock-mediated attenuation and upregulation influenced lipid synthesis and affected the levels of adipogenic transcriptional factors, C/EBP-β, C/EBP-α, PPAR-γ, and FABP4, both in vivo and in vitro (primary adipose-derived stromal cells and 3T3-L1 cells). Chromatin immunoprecipitation (ChIP) assay, reporter gene assay, and serum shock assay found that Clock transcriptionally regulated the glucocorticoid-induced leucine zipper (GILZ). Furthermore, GILZ attenuation could relieve the inhibitory effect of Clock on lipid synthesis and GILZ overexpression also reduced the promotion role of Clock attenuation in adipogenesis suggesting that Clock inhibits adipogenic differentiation of preadipocytes via GILZ. The current results demonstrate how circadian genes are likely to regulate adiposity, affecting the adipogenic differentiation process, as well as, increasing the fat cells number. Therefore, this study may provide novel insights into the underlying mechanism explaining the correlation between Clock mutation and adiposity.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™

  • The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity. 22342842

    Circadian rhythms refer to biologic processes that oscillate with a period of ~24 hr. These rhythms are sustained by a molecular clock and provide a temporal matrix that ensures the coordination of homeostatic processes with the periodicity of environmental challenges. We demonstrate the circadian molecular clock controls the expression and function of Toll-like receptor 9 (TLR9). In a vaccination model using TLR9 ligand as adjuvant, mice immunized at the time of enhanced TLR9 responsiveness presented weeks later with an improved adaptive immune response. In a TLR9-dependent mouse model of sepsis, we found that disease severity was dependent on the timing of sepsis induction, coinciding with the daily changes in TLR9 expression and function. These findings unveil a direct molecular link between the circadian and innate immune systems with important implications for immunoprophylaxis and immunotherapy.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™

  • A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα. 21874017

    Oligophrenin-1 regulates dendritic spine morphology in the brain. Mutations in the oligophrenin-1 gene (OPHN1) cause intellectual disability. We discovered a previously unknown partner of oligophrenin-1, Rev-erbα, a nuclear receptor that represses the transcription of circadian oscillators. We found that oligophrenin-1 interacts with Rev-erbα in the mouse brain, causing it to locate to dendrites, reducing its repressor activity and protecting it from degradation. Our results indicate the presence of a circadian oscillator in the hippocampus, involving the clock gene Bmal1 (also known as Arntl), that is modulated by Rev-erbα and requires oligophrenin-1 for normal oscillation. We also found that synaptic activity induced Rev-erbα localization to dendrites and spines, a process that is mediated by AMPA receptor activation and requires oligophrenin-1. Our data reveal new interactions between synaptic activity and circadian oscillators, and delineate a new means of communication between nucleus and synapse that may provide insight into normal plasticity and the etiology of intellectual disability.
    Document Type:
    Reference
    Product Catalog Number:
    07-645
    Product Catalog Name:
    Anti-Sp1 Antibody