A Critical Role for FBXW8 and MAPK in Cyclin D1 Degradation and Cancer Cell Proliferation

Cyclin D1 regulates G1 progression. Its transcriptional regulation is well understood. However, the mechanism underlying cyclin D1 ubiquitination and its subsequent degradation is not yet clear. We report that cyclin D1 undergoes increased degradation in the cytoplasm during S phase in a variety of cancer cells. This is mediated by phosphorylation at Thr286 through the activity of the Ras/Raf/MEK/ERK cascade and the F-box protein FBXW8, which is an E3 ligase. The majority of FBXW8 is expressed in the cytoplasm during G1 and S phase. In contrast, cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm in S phase. Increased cyclin D1 degradation is linked to association with FBXW8 in the cytoplasm, and enhanced phosphorylation of cyclin D1 through sustained ERK1/2 signaling. Depletion of FBXW8 caused a significant accumulation of cyclin D1, as well as sequestration of CDK1 in the cytoplasm. This resulted in a severe reduction of cell proliferation. These effects could be rescued by constitutive nuclear expression of cyclin D1-T286A. Thus, FBXW8 plays an essential role in cancer cell proliferation through proteolysis of cyclin D1. It may present new opportunities to develop therapies targeting destruction of cyclin D1 or its regulator E3 ligase selectively

Efficacy of acupuncture for chronic low back pain: protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Chronic back pain is a major public health problem and the primary reason patients seek acupuncture treatment. Therefore, an objective assessment of acupuncture efficacy is critical for making informed decisions about its appropriate role for patients with this common condition. This study addresses methodological shortcomings that have plagued previous studies evaluating acupuncture for chronic low back pain.</p> <p>Methods and Design</p> <p>A total of 640 participants (160 in each of four arms) between the ages of 18 and 70 years of age who have low back pain lasting at least 3 months will be recruited from integrated health care delivery systems in Seattle and Oakland. They will be randomized to one of two forms of Traditional Chinese Medical (TCM) acupuncture needling (individualized or standardized), a "control" group (simulated acupuncture), or to continued usual medical care. Ten treatments will be provided over 7 weeks. Study participants and the "Diagnostician" acupuncturists who evaluate participants and propose individualized treatments will be masked to the acupuncture treatment actually assigned each participant. The "Therapist" acupuncturists providing the treatments will not be masked but will have limited verbal interaction with participants. The primary outcomes, standard measures of dysfunction and bothersomeness of low back pain, will be assessed at baseline, and after 8, 26, and 52 weeks by telephone interviewers masked to treatment assignment. General health status, satisfaction with back care, days of back-related disability, and use and costs of healthcare services for back pain will also be measured. The primary analysis comparing outcomes by randomized treatment assignment will be analysis of covariance adjusted for baseline value. For both primary outcome measures, this trial will have 99% power to detect the presence of a minimal clinically significant difference among all four treatment groups and over 80% power for most pairwise comparisons. Secondary analyses will compare the proportions of participants in each group that improve by a clinically meaningful amount.</p> <p>Conclusion</p> <p>Results of this trial will help clarify the value of acupuncture needling as a treatment for chronic low back pain.</p> <p>Trial registration</p> <p>Clinical Trials.gov NCT00065585.</p

Phenotypic redshifts with self-organizing maps: A novel method to characterize redshift distributions of source galaxies for weak lensing

Wide-field imaging surveys such as the Dark Energy Survey (DES) rely on coarse measurements of spectral energy distributions in a few filters to estimate the redshift distribution of source galaxies. In this regime, sample variance, shot noise, and selection effects limit the attainable accuracy of redshift calibration and thus of cosmological constraints. We present a new method to combine wide-field, few-filter measurements with catalogs from deep fields with additional filters and sufficiently low photometric noise to break degeneracies in photometric redshifts. The multi-band deep field is used as an intermediary between wide-field observations and accurate redshifts, greatly reducing sample variance, shot noise, and selection effects. Our implementation of the method uses self-organizing maps to group galaxies into phenotypes based on their observed fluxes, and is tested using a mock DES catalog created from N-body simulations. It yields a typical uncertainty on the mean redshift in each of five tomographic bins for an idealized simulation of the DES Year 3 weak-lensing tomographic analysis of $\sigma_{\Delta z} = 0.007$, which is a 60% improvement compared to the Year 1 analysis. Although the implementation of the method is tailored to DES, its formalism can be applied to other large photometric surveys with a similar observing strategy.Comment: 24 pages, 11 figures; matches version accepted to MNRA

Expression and subcellular localization of cyclin D1 protein in epithelial ovarian tumour cells

The expression of cyclin D1 protein in tumour sections from 81 patients with epithelial ovarian cancer was analysed using immunohistochemistry. The tumours that overexpressed cyclin D1 in more than 10% of neoplastic cells were considered positive. Thus overexpression of cyclin D1 was observed in 72/81 (89%) of the cases examined. Protein was detected in both the nucleus and the cytoplasm in 24/81 (30%) and localized exclusively in the cytoplasm in 48/81 (59%) of the tumours. Cyclin D1 was overexpressed in both borderline and invasive tumours. There was no association between protein overexpression and tumour stage and differentiation. Furthermore, no correlation between cyclin D1 expression and clinical outcome was observed. However, in tumours overexpressing cyclin D1 (n = 72), the proportion displaying exclusively cytoplasmic localization of protein was higher in those with serous compared with non-serous histology (P = 0.004, odds ratio 4.8, 95% confidence interval 1.4–19.1). Western analysis using a monoclonal antibody to cyclin D1 identified a 36 kDa protein in homogenates from seven tumours displaying cytoplasmic only and one tumour demonstrating both nuclear and cytoplasmic immunostaining. Using restriction fragment length polymorphism polymerase chain reaction and PCR-multiplex analysis, amplification of the cyclin D1 gene (CCNDI) was detected in 1/29 of the tumours demonstrating overexpression of cyclin D1 protein. We conclude that deregulation of CCND1 expression leading to both cytoplasmic and nuclear protein localization is a frequent event in ovarian cancer and occurs mainly in the absence of gene amplification. © 1999 Cancer Research Campaig

Cell cyclins: triggering elements of cancer or not?

Cyclins are indispensable elements of the cell cycle and derangement of their function can lead to cancer formation. Recent studies have also revealed more mechanisms through which cyclins can express their oncogenic potential. This review focuses on the aberrant expression of G1/S cyclins and especially cyclin D and cyclin E; the pathways through which they lead to tumour formation and their involvement in different types of cancer. These elements indicate the mechanisms that could act as targets for cancer therapy

Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk

<p>Abstract</p> <p>Background</p> <p>Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription.</p> <p>Methods</p> <p>In this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins.</p> <p>Results</p> <p>Here, we have shown that the high enzymatic activity genotype of CCND1^High(AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0–1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01–1.84)]. The heterozygous COMT^Medium(MetVal) and the high enzymatic activity of COMT^High(ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07–1.68)] and [OR: 1.4, 95%CI (1.07–1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMT^High(ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73–1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: <b>2.22</b>, 95%CI (1.49–3.28)] and Finland [OR: <b>1.73</b>, 95%CI (1.08–2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity.</p> <p>Conclusion</p> <p>Using two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition.</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal