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Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells.
MicroRNAs are often associated with the pathogenesis of many cancers, including head and neck squamous cell carcinoma (HNSCC). In particular, microRNA-21 (miR-21) appears to have a critical role in tumor cell survival, chemoresistance and HNSCC progression. In this study, we investigated matrix hyaluronan (HA)-induced CD44 (a primary HA receptor) interaction with the stem cell markers, Nanog and Stat-3, in HNSCC cells (HSC-3 cells). Our results indicate that HA binding to CD44 promotes Nanog-Stat-3 (also tyrosine phosphorylated Stat-3) complex formation, nuclear translocation and transcriptional activation. Further analyses reveal that miR-21 is controlled by an upstream promoter containing Stat-3 binding site(s), while chromatin immunoprecipitation assays demonstrate that stimulation of miR-21 expression by HA/CD44 signaling is Nanog/Stat-3-dependent in HNSCC cells. This process results in a decrease of a tumor suppressor protein (PDCD4), and an upregulation of i nhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in HSC-3 cells. Treatment of HSC-3 cells with Nanog- and/or Stat-3-specific small interfering RNAs effectively blocks HA-mediated Nanog-Stat-3 signaling events, abrogates miR-21 production and increases PDCD4 expression. Subsequently, this Nanog-Stat-3 signaling inhibition causes downregulation of survival protein (IAP) expression and enhancement of chemosensitivity. To further evaluate the role of miR-21 in tumor cell-specific functions, HSC-3 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and block its target functions. Our results demonstrate that anti-miR-21 inhibitor not only upregulates PDCD4 expression but also decreases IAP expression and enhances chemosensitivity in HA-treated HNSCC cells. Together, these findings indicate that the HA-induced CD44 interaction with Nanog and Stat-3 has a pivotal role in miR-21 production leading to PDCD4 reduction, IAP upregulation and chemoresistance in HNSCC cells. This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC
Collective T- and P- Odd Electromagnetic Moments in Nuclei with Octupole Deformations
Parity and time invariance violating forces produce collective P- and T- odd
moments in nuclei with static octupole deformation. Collective Schiff moment,
electric octupole and dipole and also magnetic quadrupole appear due to the
mixing of rotational levels of opposite parity and can exceed single-particle
moments by more than a factor of 100. This enhancement is due to two factors,
the collective nature of the intrinsic moments and the small energy separation
between members of parity doublets. The above moments induce T- and P- odd
effects in atoms and molecules. Experiments with such systems may improve
substantially the limits on time reversal violation.Comment: 9 pages, Revte
Nearby Doorways, Parity Doublets and Parity Mixing in Compound Nuclear States
We discuss the implications of a doorway state model for parity mixing in
compound nuclear states. We argue that in order to explain the tendency of
parity violating asymmetries measured in Th to have a common sign,
doorways that contribute to parity mixing must be found in the same energy
neighbourhood of the measured resonance. The mechanism of parity mixing in this
case of nearby doorways is closely related to the intermediate structure
observed in nuclear reactions in which compound states are excited. We note
that in the region of interest (Th) nuclei exhibit octupole
deformations which leads to the existence of nearby parity doublets. These
parity doublets are then used as doorways in a model for parity mixing. The
contribution of such mechanism is estimated in a simple model.Comment: 11 pages, REVTE
Theory of parity violation in compound nuclear states; one particle aspects
In this work we formulate the reaction theory of parity violation in compound
nuclear states using Feshbach's projection operator formalism. We derive in
this framework a complete set of terms that contribute to the longitudinal
asymmetry measured in experiments with polarized epithermal neutrons. We also
discuss the parity violating spreading width resulting from this formalism. We
then use the above formalism to derive expressions which hold in the case when
the doorway state approximation is introduced. In applying the theory we limit
ourselves in this work to the case when the parity violating potential and the
strong interaction are one-body. In this approximation, using as the doorway
the giant spin-dipole resonance and employing well known optical potentials and
a time-reversal even, parity odd one-body interaction we calculate or estimate
the terms we derived. In our calculations we explicitly orthogonalize the
continuum and bound wave functions. We find the effects of orthogonalization to
be very important. Our conclusion is that the present one-body theory cannot
explain the average longitudinal asymmetry found in the recent polarized
neutron experiments. We also confirm the discrepancy, first pointed out by
Auerbach and Bowman, that emerges, between the calculated average asymmetry and
the parity violating spreading width, when distant doorways are used in the
theory.Comment: 37 pages, REVTEX, 5 figures not included (Postscript, available from
the authors
Time invariance violating nuclear electric octupole moments
The existence of a nuclear electric octupole moment (EOM) requires both
parity and time invariance violation. The EOMs of odd nuclei that are
induced by a particular T- and P-odd interaction are calculated. We compare
such octupole moments with the collective EOMs that can occur in nuclei having
a static octupole deformation. A nuclear EOM can induce a parity and time
invariance violating atomic electric dipole moment, and the magnitude of this
effect is calculated. The contribution of a nuclear EOM to such a dipole moment
is found, in most cases, to be smaller than that of other mechanisms of atomic
electric dipole moment production.Comment: Uses RevTex, 25 page
Nuclear Octupole Correlations and the Enhancement of Atomic Time-Reversal Violation
We examine the time-reversal-violating nuclear ``Schiff moment'' that induces
electric dipole moments in atoms. After presenting a self-contained derivation
of the form of the Schiff operator, we show that the distribution of Schiff
strength, an important ingredient in the ground-state Schiff moment, is very
different from the electric-dipole-strength distribution, with the Schiff
moment receiving no strength from the giant dipole resonance in the
Goldhaber-Teller model. We then present shell-model calculations in light
nuclei that confirm the negligible role of the dipole resonance and show the
Schiff strength to be strongly correlated with low-lying octupole strength.
Next, we turn to heavy nuclei, examining recent arguments for the strong
enhancement of Schiff moments in octupole-deformed nuclei over that of 199Hg,
for example. We concur that there is a significant enhancement while pointing
to effects neglected in previous work (both in the octupole-deformed nuclides
and 199Hg) that may reduce it somewhat, and emphasizing the need for
microscopic calculations to resolve the issue. Finally, we show that static
octupole deformation is not essential for the development of collective Schiff
moments; nuclei with strong octupole vibrations have them as well, and some
could be exploited by experiment.Comment: 25 pages, 4 figures embedded in tex
A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype
PubMed ID: 23555276This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Effect of HIP/ribosomal protein L29 deficiency on mineral properties of murine bones and teeth
Mice lacking HIP/RPL29, a component of the ribosomal machinery, display increased bone fragility. To understand the effect of sub-efficient protein synthetic rates on mineralized tissue quality, we performed dynamic and static histomorphometry and examined the mineral properties of both bones and teeth in HIP/RPL29 knock-out mice using Fourier transform infrared imaging (FTIRI). While loss of HIP/RPL29 consistently reduced total bone size, decreased mineral apposition rates were not significant, indicating that short stature is not primarily due to impaired osteoblast function. Interestingly, our microspectroscopic studies showed that a significant decrease in collagen crosslinking during maturation of HIP/RPL29-null bone precedes an overall enhancement in the relative extent of mineralization of both trabecular and cortical adult bones. This report provides strong genetic evidence that ribosomal insufficiency induces subtle organic matrix deficiencies which elevates calcification. Consistent with the HIP/RPL29-null bone phenotype, HIP/RPL29-deficient teeth also showed reduced geometric properties accompanied with relative increased mineral densities of both dentin and enamel. Increased mineralization associated with enhanced tissue fragility related to imperfection in organic phase microstructure evokes defects seen in matrix protein-related bone and tooth diseases. Thus, HIP/RPL29 mice constitute a new genetic model for studying the contribution of global protein synthesis in the establishment of organic and inorganic phases in mineral tissues
Probing exotic phenomena at the interface of nuclear and particle physics with the electric dipole moments of diamagnetic atoms: A unique window to hadronic and semi-leptonic CP violation
The current status of electric dipole moments of diamagnetic atoms which
involves the synergy between atomic experiments and three different theoretical
areas -- particle, nuclear and atomic is reviewed. Various models of particle
physics that predict CP violation, which is necessary for the existence of such
electric dipole moments, are presented. These include the standard model of
particle physics and various extensions of it. Effective hadron level combined
charge conjugation (C) and parity (P) symmetry violating interactions are
derived taking into consideration different ways in which a nucleon interacts
with other nucleons as well as with electrons. Nuclear structure calculations
of the CP-odd nuclear Schiff moment are discussed using the shell model and
other theoretical approaches. Results of the calculations of atomic electric
dipole moments due to the interaction of the nuclear Schiff moment with the
electrons and the P and time-reversal (T) symmetry violating
tensor-pseudotensor electron-nucleus are elucidated using different
relativistic many-body theories. The principles of the measurement of the
electric dipole moments of diamagnetic atoms are outlined. Upper limits for the
nuclear Schiff moment and tensor-pseudotensor coupling constant are obtained
combining the results of atomic experiments and relativistic many-body
theories. The coefficients for the different sources of CP violation have been
estimated at the elementary particle level for all the diamagnetic atoms of
current experimental interest and their implications for physics beyond the
standard model is discussed. Possible improvements of the current results of
the measurements as well as quantum chromodynamics, nuclear and atomic
calculations are suggested.Comment: 46 pages, 19 tables and 16 figures. A review article accepted for
EPJ
The CPT1C 5′UTR Contains a Repressing Upstream Open Reading Frame That Is Regulated by Cellular Energy Availability and AMPK
BACKGROUND:
Translational control is utilized as a means of regulating gene expression in many species. In most cases, posttranscriptional regulatory mechanisms play an important role in stress response pathways and can lead to dysfunctional physiology if blocked by mutations. Carnitine Palmitoyltransferase 1 C (CPT1C), the brain-specific member of the CPT 1 family, has previously been shown to be involved in regulating metabolism in situations of energy surplus.
PRINCIPAL FINDINGS:
Sequence analysis of the CPT1C mRNA revealed that it contains an upstream open reading frame (uORF) in the 5' UTR of its mRNA. Using CPT1C 5' UTR/luciferase constructs, we investigated the role of the uORF in translational regulation. The results presented here show that translation from the CPT1C main open reading frame (mORF) is repressed by the presence of the uORF, that this repression is relieved in response to specific stress stimuli, namely glucose deprivation and palmitate-BSA treatment, and that AMPK inhibition can relieve this uORF-dependent repression.
SIGNIFICANCE:
The fact that the mORF regulation is relieved in response to a specific set of stress stimuli rather than general stress response, hints at an involvement of CPT1C in cellular energy-sensing pathways and provides further evidence for a role of CPT1C in hypothalamic regulation of energy homeostasis
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