Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells

Background Although MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer. Methods Using small interfering RNA (siRNA), MYC expression was depleted in 26 human breast cancer cell lines and cell proliferation evaluated by BrdU incorporation. MYC-dependent and MYC-independent cell lines were classified based on their sensitivity to siRNA-mediated MYC knockdown. We then inhibited CDKs including CDK4/6, CDK2 and CDK1 individually using either RNAi or small molecule inhibitors, and compared sensitivity to CDK inhibition with MYC dependence in breast cancer cells. Results Breast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC protein expression and MYC phosphorylation level. Sensitivity to siRNA-mediated MYC knockdown did not parallel sensitivity to the CDK4/6 inhibitor PD0332991; instead MYC-independent cell lines were generally sensitive to PD0332991. Cell cycle arrest induced by MYC knockdown was accompanied by a decrease in CDK2 activity, but inactivation of CDK2 did not selectively affect the viability of MYC-dependent breast cancer cells. In contrast, CDK1 inactivation significantly induced apoptosis and reduced viability of MYC-dependent cells but not MYC- independent cells. This selective induction of apoptosis by CDK1 inhibitors was associated with up-regulation of the pro-apoptotic molecule BIM and was p53-independent. Conclusions Overall, these results suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer is warranted.</p

Structural determination of archaeal UDP-N-acetylglucosamine 4-epimerase from Methanobrevibacter ruminantium M1 in complex with the bacterial cell wall intermediate UDP-N-acetylmuramic acid

The crystal structure of UDP-N-acetylglucosamine 4-epimerase (UDP-GlcNAc 4-epimerase; WbpP; EC 5.1.3.7), from the archaeal methanogen Methanobrevibacter ruminantium strain M1, was determined to a resolution of 1.65 Å. The structure, with a single monomer in the crystallographic asymmetric unit, contained a conserved N-terminal Rossmann fold for nucleotide binding and an active site positioned in the C-terminus. UDP-GlcNAc 4-epimerase is a member of the short-chain dehydrogenase/reductase superfamily, sharing sequence motifs and structural elements characteristic of this family of oxidoreductases and bacterial 4-epimerases. The protein was co-crystallized with coenzyme NADH and UDP-N-acetylmuramic acid, the latter an unintended inclusion and well known product of the bacterial enzyme MurB and a critical intermediate for bacterial cell wall synthesis. This is a non-native UDP sugar amongst archaea and was most likely incorporated from the Eschericha coli expression host during purification of the recombinant enzyme

On a Matrix Model of Level Structure

We generalize the dimensionally reduced Yang-Mills matrix model by adding d=1 Chern-Simons term and terms for a bosonic vector. The coefficient, \kappa of the Chern-Simons term must be integer, and hence the level structure. We show at the bottom of the Yang-Mills potential, the low energy limit, only the linear motion is allowed for D0 particles. Namely all the particles align themselves on a single straight line subject to \kappa^2/r^2 repulsive potential from each other. We argue the relevant brane configuration to be D0-branes in a D4 after \kappa of D8's pass the system.Comment: 1+6 pages, No figure, LaTeX; Minor changes; To appear in Class. Quant. Gra

Dusty, Radiation Pressure Dominated Photoionization. II. Multi-Wavelength Emission Line Diagnostics for Narrow Line Regions

Seyfert narrow line region (NLR) emission line ratios are remarkably uniform, displaying only ~0.5 dex variation between galaxies, and even less within an individual object. Previous photoionization and shock models of this region were unable to explain this observation without the introduction of arbitrary assumptions or additional parameters. Dusty, radiation pressure dominated photoionization models provide a simple physical mechanism which can reproduce this spectral uniformity between different objects. In the first paper of this series we described this model and its implementation in detail, as well as presenting grids of model emission lines and examining the model structures. Here we explore these models further, demonstrating their ability to reproduce the observed Seyfert line ratios on standard line diagnostic diagrams in both the optical and UV. We also investigate the effects that the variation of metallicity, density and ionizing spectrum have upon both the new paradigm and the standard photoionization models used hitherto. Along with the standard diagnostic diagrams we provide several new diagnostic diagrams in the UV, Optical and IR. These new diagrams can provide further tests of the dusty, radiation pressure photoionization paradigm as well as being used as diagnostics of the metallicity, density and ionizing spectrum of the emission line clouds.Comment: Accepted by ApJS, full pdf including figures can be obtained at http://www.mso.anu.edu.au/~bgroves/Papers/ApJS2.pd

Crossover from Fermi Liquid to Non-Fermi Liquid Behavior in a Solvable One-Dimensional Model

We consider a quantum moany-body problem in one-dimension described by a Jastrow type, characterized by an exponent $\lambda$ and a parameter $\gamma$. We show that with increasing $\gamma$, the Fermi Liquid state ($\gamma=0)$ crosses over to non-Fermi liquid states, characterized by effective "temperature".Comment: 8pp. late

A Note on Dressed S-Matrices in Models with Long-Range Interactions

The {\sl dressed} Scattering matrix describing scattering of quasiparticles in various models with long-range interactions is evaluated by means of Korepin's method\upref vek1/. For models with ${1\over\sin^2(r)}$-interactions the S-matrix is found to be a momentum-independent phase, which clearly demonstrates the ideal gas character of the quasiparticles in such models. We then determine S-matrices for some models with ${1\over\sinh^2(r)}$-interaction and find them to be in general nontrivial. For the ${1\over r^2}$-limit of the ${1\over\sinh^2(r)}$-interaction we recover trivial S-matrices, thus exhibiting a crossover from interacting to noninteracting quasiparticles. The relation of the S-matrix to fractional statistics is discussed.Comment: 18 pages, jyTeX (macro included - just TeX the file) BONN-TH-94-13, revised version: analysis of models with 1/sinh^2 interaction adde

GAPS IN THE HEISENBERG-ISING MODEL

We report on the closing of gaps in the ground state of the critical Heisenberg-Ising chain at momentum $\pi$. For half-filling, the gap closes at special values of the anisotropy $\Delta= \cos(\pi/Q)$, $Q$ integer. We explain this behavior with the help of the Bethe Ansatz and show that the gap scales as a power of the system size with variable exponent depending on $\Delta$. We use a finite-size analysis to calculate this exponent in the critical region, supplemented by perturbation theory at $\Delta\sim 0$. For rational $1/r$ fillings, the gap is shown to be closed for {\em all} values of $\Delta$ and the corresponding perturbation expansion in $\Delta$ shows a remarkable cancellation of various diagrams.Comment: 12 RevTeX pages + 4 figures upon reques