1,846 research outputs found
Role of nuclear bodies in apoptosis signalling
AbstractPromyelocytic leukemia nuclear bodies (PML NBs) are dynamic macromolecular multiprotein complexes that recruit and release a plethora of proteins. A considerable number of PML NB components play vital roles in apoptosis, senescence regulation and tumour suppression. The molecular basis by which PML NBs control these cellular responses is still just beginning to be understood. In addition to PML itself, numerous further tumour suppressors including transcriptional regulator p53, acetyl transferase CBP (CREB binding protein) and protein kinase HIPK2 (homeodomain interacting protein kinase 2) are recruited to PML NBs in response to genotoxic stress or oncogenic transformation and drive the senescence and apoptosis response by regulating p53 activity. Moreover, in response to death-receptor activation, PML NBs may act as nuclear depots that release apoptotic factors, such as the FLASH (FLICE-associated huge) protein, to amplify the death signal. PML NBs are also associated with other nuclear domains including Cajal bodies and nucleoli and share apoptotic regulators with these domains, implying crosstalk between NBs in apoptosis regulation. In conclusion, PML NBs appear to regulate cell death decisions through different, pathway-specific molecular mechanisms
WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response
Genomic instability is a hallmark of cancer. The WW domaincontaining
oxidoreductase (WWOX) is a tumor suppressor spanning
the common chromosomal fragile site FRA16D. Here, we report a
direct role ofWWOXin DNA damage response (DDR) and DNA repair.
We show that Wwox deficiency results in reduced activation of the
ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient
induction and maintenance of Îł-H2AX foci, and impaired DNA repair.
Mechanistically, we show that, upon DNA damage, WWOX accumulates
in the cell nucleus, where it interacts with ATM and enhances its
activation. Nuclear accumulation of WWOX is regulated by its K63-
linked ubiquitination at lysine residue 274, which is mediated by the
E3 ubiquitin ligase ITCH. These findings identify a novel role for the
tumor suppressor WWOX and show that loss of WWOX expression
may drive genomic instabilityWe thank Dr. Eugenio Gaudio and Dr. Sonja Matt for
technical help, Dr. Yossi Shiloh for the ataxia telangiectasia-mutated inhibitor,
and Dr. Kay Huebner for the rabbit polyclonal WW domaincontaining
oxidoreductase antibody. This study was supported by a German
Israeli Foundation Joint Grant (to T.G.H. and R.I.A.), Israeli Cancer Research
Funds (to Z.S. and R.I.A.), Deutsche Forschungsgemeinschaft Grant SFB1036
(to T.G.H.), and the Deutsche Krebshilfe (T.G.H.)
Confinement, Chiral Symmetry Breaking, and Axial Anomaly from Domain Formation at Intermediate Resolution
Based on general renormalization group arguments, Polyakov's loop-space
formalism, and recent analytical lattice arguments, suggesting, after Abelian
gauge fixing, a description of pure gluodynamics by means of a Georgi-Glashow
like model, the corresponding vacuum fields are defined in a non-local way.
Using lattice information on the gauge invariant field strength correlator in
full QCD, the resolution scale \La_b, at which these fields become relevant
in the vacuum, is determined. For SU(3) gauge theory it is found that
\La_b\sim 2.4 GeV, 3.1 GeV, and 4.2 GeV for ( MeV), ( MeV), and pure gluodynamics, repectively. Implications for the operator
product expansion of physical correlators are discussed. It is argued that the
emergence of magnetic (anti)monopoles in the vacuum at resolution \La_b is a
direct consequence of the randomness in the formation of a low entropy Higgs
condensate. This implies a breaking of chiral symmetry and a proliferation of
the axial U(1) anomaly at this scale already. Justifying Abelian projection, a
decoupling of non-Abelian gauge field fluctuations from the dynamics occurs.
The condensation of (anti)monopoles at \La_c<\La_b follows from the demand
that vacuum fields ought to have vanishing action at any resolution. As
monopoles condense they are reduced to their cores, and hence they become
massless. Apparently broken gauge symmetries at resolutions \La_c<\La\le\La_b
are restored in this process.Comment: 11 pages, 3 figure
Myocardial aging as a T-cell–mediated phenomenon
In recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissue-resident leukocytes and with an accumulation of activated CD4+ Foxp3- (forkhead box P3) IFN-Îł+ T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population.info:eu-repo/semantics/publishedVersio
Cutaneous HPV23 E6 Prevents p53 Phosphorylation through Interaction with HIPK2
Ultraviolet irradiation (UV) is the major risk factor for the development of skin cancer. Moreover, increasing evidence suggests cutaneotropic human papillomaviruses (HPV) from the beta genus to play a causal role as a co-factor in the development of cutaneous squamous cell carcinoma. Homeodomain-interacting protein kinase 2 (HIPK2) operates as a potential suppressor in skin tumorigenesis and is stabilized by UV-damage. HIPK2 is an important regulator of apoptosis, which forms a complex with the tumor suppressor p53, mediating p53 phosphorylation at Ser 46 and thus promoting pro-apoptotic gene expression. In our study, we demonstrate that cutaneous HPV23 E6 protein directly targets HIPK2 function. Accordingly, HPV23 E6 interacts with HIPK2 both in vitro and in vivo. Furthermore, upon massive UVB-damage HPV23 E6 co-localizes with endogenous HIPK2 at nuclear bodies. Functionally, we demonstrate that HPV23 E6 inhibits HIPK2-mediated p53 Ser 46 phosphorylation through enforcing dissociation of the HIPK2/p53 complex. In addition, HPV23 E6 co-accumulates with endogenous HIPK2 upon UV damage suggesting a mechanism by which HPV23 E6 keeps HIPK2 in check after UV damage. Thus, cutaneous HPV23 E6 prevents HIPK2-mediated p53 Ser 46 phosphorylation, which may favour survival of UV-damaged keratinocytes and skin carcinogenesis by apoptosis evasion
The Search for Supernova-produced Radionuclides in Terrestrial Deep-sea Archives
An enhanced concentration of 60Fe was found in a deep ocean's crust in 2004
in a layer corresponding to an age of ~2 Myr. The confirmation of this signal
in terrestrial archives as supernova-induced and detection of other
supernova-produced radionuclides is of great interest. We have identified two
suitable marine sediment cores from the South Australian Basin and estimated
the intensity of a possible signal of the supernova-produced radionuclides
26Al, 53Mn, 60Fe and the pure r-process element 244Pu in these cores. A finding
of these radionuclides in a sediment core might allow to improve the time
resolution of the signal and thus to link the signal to a supernova event in
the solar vicinity ~2 Myr ago. Furthermore, it gives an insight on
nucleosynthesis scenarios in massive stars, the condensation into dust grains
and transport mechanisms from the supernova shell into the solar system
Continuity properties of measurable group cohomology
A version of group cohomology for locally compact groups and Polish modules
has previously been developed using a bar resolution restricted to measurable
cochains. That theory was shown to enjoy analogs of most of the standard
algebraic properties of group cohomology, but various analytic features of
those cohomology groups were only partially understood.
This paper re-examines some of those issues. At its heart is a simple
dimension-shifting argument which enables one to `regularize' measurable
cocycles, leading to some simplifications in the description of the cohomology
groups. A range of consequences are then derived from this argument.
First, we prove that for target modules that are Fr\'echet spaces, the
cohomology groups agree with those defined using continuous cocycles, and hence
they vanish in positive degrees when the acting group is compact. Using this,
we then show that for Fr\'echet, discrete or toral modules the cohomology
groups are continuous under forming inverse limits of compact base groups, and
also under forming direct limits of discrete target modules.
Lastly, these results together enable us to establish various circumstances
under which the measurable-cochains cohomology groups coincide with others
defined using sheaves on a semi-simplicial space associated to the underlying
group, or sheaves on a classifying space for that group. We also prove in some
cases that the natural quotient topologies on the measurable-cochains
cohomology groups are Hausdorff.Comment: 52 pages. [Nov 22, 2011:] Major re-write with Calvin C. Moore as new
co-author. Results from previous version strengthened and several new results
added. [Nov 25, 2012:] Final version now available at springerlink.co
Relativistic deformed mean-field calculation of binding energy differences of mirror nuclei
Binding energy differences of mirror nuclei for A=15, 17, 27, 29, 31, 33, 39
and 41 are calculated in the framework of relativistic deformed mean-field
theory. The spatial components of the vector meson fields and the photon are
fully taken into account in a self-consistent manner. The calculated binding
energy differences are systematically smaller than the experimental values and
lend support to the existency of the Okamoto--Nolen-Schiffer anomaly found
decades ago in nonrelativistic calculations. For the majority of the nuclei
studied, however, the results are such that the anomaly is significantly
smaller than the one obtained within state-of-the-art nonrelativistic
calculations.Comment: 13 pages, REVTeX, no figure
Low-Energy \Lambda-\p Scattering Parameters from the Reaction
Constraints on the spin-averaged scattering length and effective
range have been obtained from measurements of the reaction
close to the production threshold by comparing model phase-space Dalitz plot
occupations with experimental ones. The data fix well the position of the
virtual bound state in the system. Combining this with information
from elastic scattering measurements at slightly higher energies,
together with the fact that the hyperdeuteron is not bound, leads to a new
determination of the low energy scattering parameters.Comment: 18 pages, 7 figure
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BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition.
Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones
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