64 research outputs found
Activation of mitogen-activated protein kinases by peroxisome proliferator-activated receptor ligands: an example of nongenomic signaling
ABSTRACT Peroxisome proliferator-activated receptors (PPARs) are a subfamily of nuclear hormone receptors that function as ligandactivated transcription factors to regulate lipid metabolism and homeostasis. In addition to their ability to promote gene transcription in a PPAR-dependent manner, ligands for this receptor family have recently been shown to induce mitogen-activated protein kinase (MAPK) phosphorylation. It is noteworthy that the transcriptional changes induced by PPAR ligands can be separated into distinct PPAR-and MAPK-dependent signaling pathways, suggesting that MAPKs alone mediate some of the effects of PPAR agonists in a nongenomic manner. This review will highlight recent studies that elucidate the nongenomic mechanisms of PPAR ligand-induced MAPK phosphorylation. The potential relevance of MAPK signaling in PPAR biology is also discussed
Peroxisome Proliferator-activated Receptor Îł-independent Activation of p38 MAPK by Thiazolidinediones Involves Calcium/Calmodulin-dependent Protein Kinase II and Protein Kinase R: CORRELATION WITH ENDOPLASMIC RETICULUM STRESS
The thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligands that promote increased insulin sensitivity in type II diabetic patients. In addition to their ability to improve glucose homeostasis, TZDs also exert anti-proliferative effects by a mechanism that is unclear. Our laboratory has shown that two TZDs, ciglitazone and troglitazone, rapidly induce calcium-dependent p38 mitogen-activated protein kinase (MAPK) phosphorylation in liver epithelial cells. Here, we further characterize the mechanism responsible for p38 MAPK activation by PPARgamma ligands and correlate this with the induction of endoplasmic reticulum (ER) stress. Specifically, we show that TZDs rapidly activate the ER stress-responsive pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase or PKR (double-stranded RNA-activated protein kinase)-like endoplasmic reticulum kinase/pancreatic eIF2alpha kinase, and that activation of these kinases is correlated with subsequent eIF2alpha phosphorylation. Interestingly, PPARgamma ligands not only activated calcium/calmodulin-dependent kinase II (CaMKII) 2-fold over control, but the selective CaMKII inhibitor, KN-93, attenuated MKK3/6 and p38 as well as PKR and eIF2alpha phosphorylation. Although CaMKII was not affected by inhibition of PKR with 2-aminopurine, phosphorylation of MKK3/6 and p38 as well as eIF2alpha were significantly reduced. Collectively, these data provide evidence that CaMKII is a regulator of PKR-dependent p38 and eIF2alpha phosphorylation in response to ER calcium depletion by TZDs. Furthermore, using structural derivatives of TZDs that lack PPARgamma ligand-binding activity as well as a PPARgamma antagonist, we show that activation of these kinase signaling pathways is PPARgamma-independent
Dependence of Peroxisome Proliferator-activated Receptor Ligand-induced Mitogen-activated Protein Kinase Signaling on Epidermal Growth Factor Receptor Transactivation
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that function as ligand-activated transcription factors regulating lipid metabolism and homeostasis. In addition to their ability to regulate PPAR-mediated gene transcription, PPARalpha and gamma ligands have recently been shown to induce activation of mitogen-activated protein kinases (MAPKs), which in turn phosphorylate PPARs, thereby affecting transcriptional activity. However, the mechanism for PPAR ligand-dependent MAPK activation is unclear. In the current study, we demonstrate that various PPARalpha (nafenopin) and gamma (ciglitazone and troglitazone) agonists rapidly induced extracellular signal-regulated kinase (Erk) and/or p38 phosphorylation in rat liver epithelial cells (GN4). The selective epidermal growth factor receptor (EGFR) kinase inhibitors, PD153035 and ZD1839 (Iressa), abolished PPARalpha and gamma agonist-dependent Erk activation. Consistent with this, PPAR agonists increased tyrosine autophosphorylation of the EGFR as well as phosphorylation at a putative Src-specific site, Tyr845. Experiments with the Src inhibitor, PP2, and the antioxidant N-acetyl-L-cysteine revealed critical roles for Src and reactive oxygen species as upstream mediators of EGFR transactivation in response to PPAR ligands. Moreover, PPARalpha and gamma ligands increased Src autophosphorylation as well as kinase activity. EGFR phosphorylation, in turn, led to Ras-dependent Erk activation. In contrast, p38 activation by PPARalpha and gamma ligands occurred independently of Src, oxidative stress, the EGFR, and Ras. Interestingly, PPARalpha and gamma agonists caused rapid activation of proline-rich tyrosine kinase or Pyk2; Pyk2 as well as p38 phosphorylation was reduced by intracellular Ca2+ chelation without an observable effect on EGFR and Erk activation, suggesting a possible role for Pyk2 as an upstream activator of p38. In summary, PPARalpha and gamma ligands activate two distinct signaling cascades in GN4 cells leading to MAPK activation
Auto-inhibition of the Dbl Family Protein Tim by an N-terminal Helical Motif
Dbl-related oncoproteins are guanine nucleotide exchange factors specific for Rho-family GTPases and typically possess tandem Dbl homology (DH) and pleckstrin homology domains that act in concert to catalyze exchange. Because the ability of many Dbl-family proteins to catalyze exchange is constitutively activated by truncations N-terminal to their DH domains, it has been proposed that the activity of Dbl-family proteins is regulated by auto-inhibition. However, the exact mechanisms of regulation of Dbl-family proteins remain poorly understood. Here we show that the Dbl-family protein, Tim, is auto-inhibited by a short, helical motif immediately N-terminal to its DH domain, which directly occludes the catalytic surface of the DH domain to prevent GTPase activation. Similar to the distantly related Vav isozymes, auto-inhibition of Tim is relieved by truncation, mutation, or phosphorylation of the auto-inhibitory helix. A peptide comprising the helical motif inhibits the exchange activity of Tim in vitro. Furthermore, substitutions within the most highly conserved surface of the DH domain designed to disrupt interactions with the auto-inhibitory helix also activate the exchange process
CEERS: Diversity of Lyman-Alpha Emitters during the Epoch of Reionization
We analyze rest-frame ultraviolet to optical spectra of three -
galaxies whose Ly-emission lines were previously detected with
Keck/MOSFIRE observations, using the JWST/NIRSpec observations from the Cosmic
Evolution Early Release Science (CEERS) survey. From NIRSpec data, we confirm
the systemic redshifts of these Ly emitters, and emission-line ratio
diagnostics indicate these galaxies were highly ionized and metal poor. We
investigate Ly line properties, including the line flux, velocity
offset, and spatial extension. For the one galaxy where we have both NIRSpec
and MOSFIRE measurements, we find a significant offset in their flux
measurements ( greater in MOSFIRE) and a marginal difference in
the velocity shifts. The simplest interpretation is that the Ly
emission is extended and not entirely encompassed by the NIRSpec slit. The
cross-dispersion profiles in NIRSpec reveal that Ly in one galaxy is
significantly more extended than the non-resonant emission lines. We also
compute the expected sizes of ionized bubbles that can be generated by the
Ly sources, discussing viable scenarios for the creation of sizable
ionized bubbles (1 physical Mpc). The source with the highest-ionization
condition is possibly capable of ionizing its own bubble, while the other two
do not appear to be capable of ionizing such a large region, requiring
additional sources of ionizing photons. Therefore, the fact that we detect
Ly from these galaxies suggests diverse scenarios on escape of
Ly during the epoch of reionization. High spectral resolution spectra
with JWST/NIRSpec will be extremely useful for constraining the physics of
patchy reionization.Comment: Submitted to ApJ (18 pages, 7 figures, 2 tables
Differential Kinetics of Immune Responses Elicited by Covid-19 Vaccines
To the Editor: Previous studies have shown that the BNT162b2 (PfizerâBioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & JohnsonâJanssen) vaccines provide robust protective efficacy against coronavirus disease 2019 (Covid-19). Here, we report comparative kinetics of humoral and cellular immune responses elicited by the two-dose BNT162b2 vaccine (in 31 participants), the two-dose mRNA-1273 vaccine (in 22 participants), and the one-dose Ad26.COV2.S vaccine (in 8 participants). We evaluated antibody and T-cell responses from peak immunity at 2 to 4 weeks after the second immunization in recipients of the messenger RNA (mRNA) vaccines or after the first immunization in recipients of the Ad26.COV2.S vaccine to 8 months (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org)
Identification of Hammerhead Ribozymes in All Domains of Life Reveals Novel Structural Variations
Hammerhead ribozymes are small self-cleaving RNAs that promote strand scission by internal phosphoester transfer. Comparative sequence analysis was used to identify numerous additional representatives of this ribozyme class than were previously known, including the first representatives in fungi and archaea. Moreover, we have uncovered the first natural examples of âtype IIâ hammerheads, and our findings reveal that this permuted form occurs in bacteria as frequently as type I and III architectures. We also identified a commonly occurring pseudoknot that forms a tertiary interaction critical for high-speed ribozyme activity. Genomic contexts of many hammerhead ribozymes indicate that they perform biological functions different from their known role in generating unit-length RNA transcripts of multimeric viroid and satellite virus genomes. In rare instances, nucleotide variation occurs at positions within the catalytic core that are otherwise strictly conserved, suggesting that core mutations are occasionally tolerated or preferred
CANDELS: The Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey - The Hubble Space Telescope Observations, Imaging Data Products and Mosaics
This paper describes the Hubble Space Telescope imaging data products and
data reduction procedures for the Cosmic Assembly Near-IR Deep Extragalactic
Legacy Survey (CANDELS). This survey is designed to document the evolution of
galaxies and black holes at , and to study Type Ia SNe beyond
. Five premier multi-wavelength sky regions are selected, each with
extensive multiwavelength observations. The primary CANDELS data consist of
imaging obtained in the Wide Field Camera 3 / infrared channel (WFC3/IR) and
UVIS channel, along with the Advanced Camera for Surveys (ACS). The
CANDELS/Deep survey covers \sim125 square arcminutes within GOODS-N and
GOODS-S, while the remainder consists of the CANDELS/Wide survey, achieving a
total of \sim800 square arcminutes across GOODS and three additional fields
(EGS, COSMOS, and UDS). We summarize the observational aspects of the survey as
motivated by the scientific goals and present a detailed description of the
data reduction procedures and products from the survey. Our data reduction
methods utilize the most up to date calibration files and image combination
procedures. We have paid special attention to correcting a range of
instrumental effects, including CTE degradation for ACS, removal of electronic
bias-striping present in ACS data after SM4, and persistence effects and other
artifacts in WFC3/IR. For each field, we release mosaics for individual epochs
and eventual mosaics containing data from all epochs combined, to facilitate
photometric variability studies and the deepest possible photometry. A more
detailed overview of the science goals and observational design of the survey
are presented in a companion paper.Comment: 39 pages, 25 figure
CANDELS: The Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey
The Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS)
is designed to document the first third of galactic evolution, over the
approximate redshift (z) range 8--1.5. It will image >250,000 distant galaxies
using three separate cameras on the Hubble Space Telescope, from the
mid-ultraviolet to the near-infrared, and will find and measure Type Ia
supernovae at z>1.5 to test their accuracy as standardizable candles for
cosmology. Five premier multi-wavelength sky regions are selected, each with
extensive ancillary data. The use of five widely separated fields mitigates
cosmic variance and yields statistically robust and complete samples of
galaxies down to a stellar mass of 10^9 M_\odot to z \approx 2, reaching the
knee of the ultraviolet luminosity function (UVLF) of galaxies to z \approx 8.
The survey covers approximately 800 arcmin^2 and is divided into two parts. The
CANDELS/Deep survey (5\sigma\ point-source limit H=27.7 mag) covers \sim 125
arcmin^2 within GOODS-N and GOODS-S. The CANDELS/Wide survey includes GOODS and
three additional fields (EGS, COSMOS, and UDS) and covers the full area to a
5\sigma\ point-source limit of H \gtrsim 27.0 mag. Together with the Hubble
Ultra Deep Fields, the strategy creates a three-tiered "wedding cake" approach
that has proven efficient for extragalactic surveys. Data from the survey are
nonproprietary and are useful for a wide variety of science investigations. In
this paper, we describe the basic motivations for the survey, the CANDELS team
science goals and the resulting observational requirements, the field selection
and geometry, and the observing design. The Hubble data processing and products
are described in a companion paper.Comment: Submitted to Astrophysical Journal Supplement Series; Revised
version, subsequent to referee repor
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
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