3,107 research outputs found
Specific Functions of the Tumor Suppressor P53 are Activated by P73 and VHL
Indiana University-Purdue University Indianapolis (IUPUI)The transcription factor and tumor suppressor protein p53 critically regulates cell
survival or death in response to cellular stress. p53 can activate genes involved in a wide
variety of processes, including apoptosis, cell cycle arrest, angiogenesis, metabolism, and
senescence. Mutations in p53 are common in cancer and alter its interactions with other
proteins, but there are other mechanisms and posttranslational modifications that can alter
these interactions as well. In some tumors, such as renal cell carcinoma, p53 is commonly
inactive even though mutations to TP53 are rare. This suggests that there are other
biochemical mechanisms of inhibition, which we explore in this study.
Mutations in the DNA-binding domain of p53 result in conformational changes
that enable p53 to interact with and inhibit its family member p73, thereby promoting cell
survival instead of apoptosis. In contrast, it has been reported that wild-type p53 does not
bind to p73. We found that JNK-mediated phosphorylation of Thr81 in the proline-rich
domain (PRD) of p53 enabled wild-type p53 to form a complex with p73. The
dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target
genes such as PUMA and BAX, as well as the induction of apoptosis. In addition to the
apoptotic function of p53, the tumor suppressor also plays a major role in the inhibition
of angiogenesis.
Here we also report a new mechanism where the Mdm2 oncoprotein can
indirectly inactive p53 through the regulation of the tumor suppressor VHL. In response
to hypoxia, VHL can bind p53, which results in activation of several anti-angiogenic targets of p53 such as THBS1 and COL18A1. Mdm2 regulates the VHL-p53 interaction
by conjugating nedd8 to VHL within a region that is important for the VHL-p53
interaction, blocking the induction of anti-angiogenic genes and resulting in a
proangiogenic phenotype. Due to its positive regulation of major proangiogenic proteins
and its negative regulation of potent inhibitors of angiogenesis, we propose that the
oncoprotein Mdm2 is the angiogenic switch. These findings refine our understanding of
p53 interactions and activation, specifically for p53-p73 induced cell death and p53-VHL
inhibition of angiogenesis.2020-08-0
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Cooling requirements fueled the collapse of a desert bird community from climate change.
Climate change threatens global biodiversity by increasing extinction risk, yet few studies have uncovered a physiological basis of climate-driven species declines. Maintaining a stable body temperature is a fundamental requirement for homeothermic animals, and water is a vital resource that facilitates thermoregulation through evaporative cooling, especially in hot environments. Here, we explore the potential for thermoregulatory costs to underlie the community collapse of birds in the Mojave Desert over the past century in response to climate change. The probability of persistence was lowest for species occupying the warmest and driest sites, which imposed the greatest cooling costs. We developed a general model of heat flux to evaluate whether water requirements for evaporative cooling contributed to species' declines by simulating thermoregulatory costs in the Mojave Desert for 50 bird species representing the range of observed declines. Bird species' declines were positively associated with climate-driven increases in water requirements for evaporative cooling and exacerbated by large body size, especially for species with animal-based diets. Species exhibiting reductions in body size across their range saved up to 14% in cooling costs and experienced less decline than species without size reductions, suggesting total cooling costs as a mechanism underlying Bergmann's rule. Reductions in body size, however, are unlikely to offset the 50 to 78% increase in cooling costs threatening desert birds from future climate change. As climate change spreads warm, dry conditions across the planet, water requirements are increasingly likely to drive population declines, providing a physiological basis for climate-driven extinctions
Propulsion in a viscoelastic fluid
Flagella beating in complex fluids are significantly influenced by
viscoelastic stresses. Relevant examples include the ciliary transport of
respiratory airway mucus and the motion of spermatozoa in the mucus-filled
female reproductive tract. We consider the simplest model of such propulsion
and transport in a complex fluid, a waving sheet of small amplitude free to
move in a polymeric fluid with a single relaxation time. We show that, compared
to self-propulsion in a Newtonian fluid occurring at a velocity U_N, the sheet
swims (or transports fluid) with velocity U / U_N = [1+De^2 (eta_s)/(eta)
]/[1+De^2], where eta_s is the viscosity of the Newtonian solvent, eta is the
zero-shear-rate viscosity of the polymeric fluid, and De is the Deborah number
for the wave motion, product of the wave frequency by the fluid relaxation
time. Similar expressions are derived for the rate of work of the sheet and the
mechanical efficiency of the motion. These results are shown to be independent
of the particular nonlinear constitutive equations chosen for the fluid, and
are valid for both waves of tangential and normal motion. The generalization to
more than one relaxation time is also provided. In stark contrast with the
Newtonian case, these calculations suggest that transport and locomotion in a
non-Newtonian fluid can be conveniently tuned without having to modify the
waving gait of the sheet but instead by passively modulating the material
properties of the liquid.Comment: 21 pages, 1 figur
Spectropolarimetry and Modeling of the Eclipsing T Tauri Star KH 15D
KH 15D is a strongly variable T Tauri star in the young star cluster NGC 2264
that shows a decrease in flux of 3.5 magnitudes lasting for 18 days and
repeating every 48 days. The eclipsing material is likely due to orbiting dust
or rocky bodies in a partial ring or warped disk that periodically occults the
star. We measured the polarized spectrum in and out of eclipse at the Keck and
Palomar observatories. Outside of the eclipse, the star exhibited low
polarization consistent with zero. During eclipse, the polarization increased
dramatically to ~2% across the optical spectrum, while the spectrum had the
same continuum shape as outside of eclipse and exhibited emission lines of much
larger equivalent width, as previously seen. From the data, we conclude that
(a) the scattering region is uneclipsed; (b) the scattering is nearly
achromatic; (c) the star is likely completely eclipsed so that the flux during
eclipse is entirely due to scattered light, a conclusion also argued for by the
shape of the ingress and egress. We argue that the scattering is not due to
electrons, but may be due to large dust grains of size ~10 micron, similar to
the interplanetary grains which scatter the zodiacal light. We construct a
warped-disk model with an extended dusty atmosphere which reproduces the main
features of the lightcurve, namely (a) a gradual decrease before ingress due to
extinction in the atmosphere (similar for egress); (b) a sharper decrease
within ingress due to the optically-thick base of the atmosphere; (c) a
polarized flux during eclipse which is 0.1% of the total flux outside of
eclipse, which requires no fine-tuning of the model. (abridged)Comment: 9 pages, 7 figures, accepted for publication in ApJ, MPEG simulation
available at http://www.astro.washington.edu/agol/scatter2.mp
The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2)
Mouse double minute 2 (Mdm2) and MdmX dimerize in response to low levels of genotoxic stress to function in a ubiquitinating complex, which signals for destabilization of p53. Under growth conditions, Mdm2 functions as a neddylating ligase, but the importance and extent of MdmX involvement in this process are largely unknown. Here we show that when Mdm2 functions as a neddylating enzyme, MdmX is stabilized. Furthermore, we demonstrate that under growth conditions, MdmX enhances the neddylation activity of Mdm2 on p53 and is a substrate for neddylation itself. Importantly, MdmX knockdown in MCF-7 breast cancer cells resulted in diminished neddylated p53, suggesting that MdmX is important for Mdm2-mediated neddylation. Supporting this finding, the lack of MdmX in transient assays or in p53/MdmX-/- MEFs results in decreased or altered neddylation of p53 respectively; therefore, MdmX is a critical component of the Mdm2-mediated neddylating complex. c-Src is the upstream activator of this Mdm2-MdmX neddylating pathway and loss of Src signaling leads to the destabilization of MdmX that is dependent on the RING (Really Interesting New Gene) domain of MdmX. Treatment with a small molecule inhibitor of neddylation, MLN4924, results in the activation of Ataxia Telangiectasia Mutated (ATM). ATM phosphorylates Mdm2, converting Mdm2 to a ubiquitinating enzyme which leads to the destabilization of MdmX. These data show how distinct signaling pathways engage neddylating or ubiquitinating activities and impact the Mdm2-MdmX axis
Mutant and wild-type p53 form complexes with p73 upon phosphorylation by the kinase JNK
The transcription factors p53 and p73 are critical to the induction of apoptotic cell death, particularly in response to cell stress that activates c-Jun N-terminal kinase (JNK). Mutations in the DNA-binding domain of p53, which are commonly seen in cancers, result in conformational changes that enable p53 to interact with and inhibit p73, thereby suppressing apoptosis. In contrast, wild-type p53 reportedly does not interact with p73. We found that JNK-mediated phosphorylation of Thr81 in the proline-rich domain (PRD) of p53 enabled wild-type p53, as well as mutant p53, to form a complex with p73. Structural algorithms predicted that phosphorylation of Thr81 exposes the DNA-binding domain in p53 to enable its binding to p73. The dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target genes [such as those encoding p53–up-regulated modulator of apoptosis (PUMA) and Bcl-2-associated X protein (BAX)] and, subsequently, the induction of apoptosis in response to JNK activation by cell stress in various cells. Thus, JNK phosphorylation of mutant and wild-type p53 promotes the formation of a p53/p73 complex that determines cell fate: apoptosis in the context of wild-type p53 or cell survival in the context of the mutant. These findings refine our current understanding of both the mechanistic links between p53 and p73 and the functional role for Thr81 phosphorylation
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