12 research outputs found
Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription.
Deregulated expression of MYC induces a dependence on the NUAK1 kinase, but the molecular mechanisms underlying this dependence have not been fully clarified. Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1. Both NUAK1 and PNUTS associate with the splicing machinery. Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis. Activation of MYC does not bypass the requirement for NUAK1 for spliceosome activity but significantly attenuates transcription inhibition. Consequently, NUAK1 inhibition in MYC-transformed cells induces global accumulation of RNAPII both at the pause site and at the first exon-intron boundary but does not increase mRNA synthesis. We suggest that NUAK1 inhibition in the presence of deregulated MYC traps non-productive RNAPII because of the absence of correctly assembled spliceosomes
Combined inhibition of Aurora-A and ATR kinase results in regression of MYCN-amplified neuroblastoma
Amplification of MYCN is the driving oncogene in a subset of high-risk neuroblastoma. The MYCN protein and the Aurora-A kinase form a complex during S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription-replication conflicts and activates the Ataxia telangiectasia and Rad3 related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR induces rampant tumor-specific apoptosis and tumor regression in mouse models of neuroblastoma, leading to permanent eradication in a subset of mice. The therapeutic efficacy is due to both tumor cell-intrinsic and immune cell-mediated mechanisms. We propose that targeting the ability of Aurora-A to resolve transcription-replication conflicts is an effective therapy for MYCN-driven neuroblastoma (141 words)
Enhanced sequential carrier capture into individual quantum dots and quantum posts controlled by surface acoustic waves
Individual self-assembled Quantum Dots and Quantum Posts are studied under
the influence of a surface acoustic wave. In optical experiments we observe an
acoustically induced switching of the occupancy of the nanostructures along
with an overall increase of the emission intensity. For Quantum Posts,
switching occurs continuously from predominantely charged excitons (dissimilar
number of electrons and holes) to neutral excitons (same number of electrons
and holes) and is independent on whether the surface acoustic wave amplitude is
increased or decreased. For quantum dots, switching is non-monotonic and shows
a pronounced hysteresis on the amplitude sweep direction. Moreover, emission of
positively charged and neutral excitons is observed at high surface acoustic
wave amplitudes. These findings are explained by carrier trapping and
localization in the thin and disordered two-dimensional wetting layer on top of
which Quantum Dots nucleate. This limitation can be overcome for Quantum Posts
where acoustically induced charge transport is highly efficient in a wide
lateral Matrix-Quantum Well.Comment: 11 pages, 5 figure
Dynamic Acoustic Control of Individual Optically Active Quantum Dot-like Emission Centers in Heterostructure Nanowires
We probe and control the optical properties of emission centers forming in
radial het- erostructure GaAs-Al0.3Ga0.7As nanowires and show that these
emitters, located in Al0.3Ga0.7As layers, can exhibit quantum-dot like
characteristics. We employ a radio frequency surface acoustic wave to
dynamically control their emission energy and occupancy state on a nanosec- ond
timescale. In the spectral oscillations we identify unambiguous signatures
arising from both the mechanical and electrical component of the surface
acoustic wave. In addition, differ- ent emission lines of a single quantum dot
exhibit pronounced anti-correlated intensity oscilla- tions during the acoustic
cycle. These arise from a dynamically triggered carrier extraction out of the
quantum dot to a continuum in the radial heterostructure. Using finite element
modeling and Wentzel-Kramers-Brillouin theory we identify quantum tunneling as
the underlying mech- anism. These simulation results quantitatively reproduce
the observed switching and show that in our systems these quantum dots are
spatially separated from the continuum by > 10.5 nm.Comment: This document is the unedited Author's version of a Submitted Work
that was subsequently accepted for publication in Nano Letters, copyright
\c{copyright} American Chemical Society after peer review. To access the
final edited and published work see
http://pubs.acs.org/doi/abs/10.1021/nl404043
Fourier synthesis of radio frequency nanomechanical pulses with different shapes
The concept of Fourier synthesis is heavily employed in both consumer
electronic products and fundamental research. In the latter, pulse shaping is
key to dynamically initialize, probe and manipulate the state of classical or
quantum systems. In nuclear magnetic resonance, for instance, shaped pulses
have a long-standing tradition and the underlying fundamental concepts have
subsequently been successfully extended to optical frequencies and even to
implement quantum gate operations. Transferring these paradigms to
nanomechanical systems requires tailored nanomechanical waveforms. Here, we
report on an additive Fourier synthesizer for nanomechanical waveforms based on
monochromatic surface acoustic waves. As a proof of concept, we electrically
synthesize four different elementary nanomechanical waveforms from a
fundamental surface acoustic wave at MHz using a superposition
of up to three discrete harmonics . We employ these shaped pulses to
interact with an individual sensor quantum dot and detect their deliberately
and temporally modulated strain component via the opto-mechanical quantum dot
response. Importantly, and in contrast to the direct mechanical actuation by
bulk piezoactuators, surface acoustic waves provide much higher frequencies (>
20 GHz) to resonantly drive mechanical motion. Thus, our technique uniquely
allows coherent mechanical control of localized vibronic modes of
optomechanical crystals, even in the quantum limit when cooled to the
vibrational ground state.Comment: 18 pages - final manuscript and supporting materia
Combined inhibition of Aurora-A and ATR kinases results in regression of MYCN-amplified neuroblastoma
Amplification of MYCN is the driving oncogenic change in a subset of high-risk neuroblastomas. The MYCN protein and the Aurora-A kinase form a complex during the S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in the S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription–replication conflicts and activates ataxia telangiectasia and Rad3-related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR kinases induces rampant tumor-specific apoptosis and tumor regression in mouse models of neuroblastoma, leading to permanent eradication in a subset of mice. The therapeutic efficacy is due to both tumor cell-intrinsic and immune cell-mediated mechanisms. We propose that targeting the ability of Aurora-A to resolve transcription–replication conflicts is an effective therapy for MYCN-driven neuroblastoma