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At least 1,009 records · Page 56Linked to original sources
PubMed2004

Adsorption of organic matter at mineral/water interfaces: 3. Implications of surface dissolution for adsorption of oxalate.

The adsorption of oxalate on a model aluminum oxide, corundum (alpha-Al2O3), has been examined over a broad range of oxalate concentrations (0.125-25.0 mM) and pH conditions (2-10). In situ attenuated total reflectance Fourier transform infrared (ATR-FTIR) measurements indicate that at low to intermediate concentrations ([oxalate] < or = 2.50 mM), oxalate adsorbs to corundum predominantly as a bidentate, mononuclear, inner-sphere complex involving both carboxyl groups. Significant contributions from outer-spherically bound oxalate and aqueous Ox(2-) are additionally observed at higher oxalate concentrations. Consistent with the ATR-FTIR findings, macroscopic adsorption data measured for oxalate concentrations of 0.125-2.50 mM can be generally well modeled with a single bidentate, inner-sphere oxalate complex using the charge distribution multisite complexation (CD-MUSIC) model. However, at intermediate oxalate concentrations (0.50 and 1.25 mM) and pH <5, the extent of oxalate adsorption measured experimentally is found to fall significantly below that predicted by CD-MUSIC simulations. The latter finding is interpreted in terms of competition for oxalate from dissolved Al(III), the formation of which is promoted by the dissolution-enhancing properties of the adsorbed oxalate anion. In accordance with this expectation, increasing concentrations of dissolved Al(III) in solution are found to significantly decrease the extent of oxalate adsorption on corundum under acidic pH conditions, presumably through promoting the formation of Al(III)-oxalate complexes with reduced affinities for the corundum surface compared with the uncomplexed oxalate anion.

Journal Article↗
PubMed2004

Surface modification of an ethylene-acrylic acid copolymer film: grafting amine-terminated linear and branched architectures.

Polymer films can be tailored for a specific application by modifying their surface properties. In this study, linear and branched architectures were grafted to ethylene-acrylic acid (EAA) copolymer films using the so-called grafting from approach. Dicyclohexylcarbodiimide was used to activate the carboxylic acid functionality on the surface of the EAA copolymer film before reacting it with selected di- and tri-amine compounds. The carboxylic acid functionality was subsequently regenerated by reacting the amine-grafted film with succinic anhydride. These reaction steps were then repeated to create the linear and branched architectures on the EAA film surface. The film surface resulting from each reaction step was analyzed using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and contact angle measurements. A systematic analysis of the ATR-FTIR results was performed to estimate the average conversion of the reaction schemes and to explain the observed contact angle results. A significant reduction in water contact angle for the EAA film grafted with a branched architecture was observed. The EAA film grafted with a linear architecture showed a marginal reduction in water contact angle when ethanol was used as a solvent for ethylenediamine. When the solvent for ethylenediamine was changed to water, the contact angle decreased noticeably. However, analysis of control films showed that the reduction in the contact angles was due to the solvent treatment. In the case of branched architectures, such reduction in contact angle due to the solvent treatment was not observed. Several control experiments were performed to ensure that the reduction in the contact angles was in fact due to the grafted species and not due to exposure to various solvents used in the reaction scheme.

Journal Article↗
PubMed2005

Correlation between the structure of water in the vicinity of carboxybetaine polymers and their blood-compatibility.

The structure and hydrogen bonding of water in the vicinity of carboxybetaine homopolymer (poly[1-carboxy-N,N-dimethyl-N-(2'-methacryloyloxyethyl)methanaminium inner salt] (PolyCMB), and a random copolymer of CMB and n-butyl methacrylate, Poly(CMB-r-BMA), with various molecular weights were analyzed in their aqueous solutions and thin film with contours of O-H stretching of Raman and attenuated total reflection infrared (ATR-IR) spectra, respectively. The relative intensity of the collective band (C value) corresponding to a long-range coupling of O-H stretchings of the Raman spectra for aqueous solution of Poly(CMB-r-BMA) was very close to that for pure water, which is in contrast with the smaller C value in aqueous solution of ordinary polyelectrolytes. The number of hydrogen bonds collapsed by the presence of one monomer residue (N(corr) value) of PolyCMB and Poly(CMB-r-BMA) (CMB, 45 mol %) (M(w), 1.14 x 10(4) and 1.78 x 10(4), respectively) could be calculated from the C value. The N(corr) values were much smaller than those for ordinary polyelectrolytes and close to those for nonionic water-soluble polymers such as poly(ethylene glycol) and poly(N-vinylpyrrolidone). Furthermore, a water-insoluble Poly(CMB-r-BMA) with a large BMA content (M(w) = 347 kD, CMB 27 mol %) could be cast as a thin film (thickness, ca. 10 microm) on a ZnSe crystal for the ATR-IR analyses. At an early stage of sorption of water into the Poly(CMB-r-BMA) film, the O-H stretching band of IR spectra for the water incorporated in the film was similar to that for free water, which is in contrast with the drastic change in the O-H stretching band of water incorporated in polymer films such as poly(methyl methacrylate) (PMMA) and poly(n-butyl methacrylate) (PBMA). The theoretical vibrational frequency for water molecules hydrating a betaine molecule calculated by using a density functional method supported the experimental results. The adhesion of human platelets to Poly(CMB-r-BMA) films was much less than that to PMMA and PBMA. With an increase in the content of CMB residue, the number of platelets adhered to the Poly(CMB-r-BMA) film drastically decreased and then gradually increased, probably due to the increase in the roughness of the film surface. These results suggest that the carboxybetaine monomer residues with a zwitterionic structure do not significantly disturb the hydrogen bonding between water molecules in both aqueous solution and thin film systems, resulting in the excellent blood-compatibility of the carboxybetaine polymers.

Betaine↗
PubMed2006

Physically self-assembled monolayers (PSAMs) of lecithin lipids at hydrophilic silicon oxide interfaces.

A new method of making physically self-assembled monolayers (PSAMs) on hydrophilic solid surfaces is presented. This method uses a mixture of a nonpolar solvent, such as hexane, and a strong polar solvent, such as ethanol, to dissolve the lipids. The deposition of two lecithin lipids, dipalmitoylphosphatidylcholine (DPPC) and dilauroylphosphatidylcholine (DLPC), has been studied. These lipids physically self-assemble, or adsorb, onto hydrophilic silicon oxide/silicon surfaces when such surfaces are in contact with the lipid solution. The adsorbed layers were probed with ex-situ attenuated total reflection infrared (ATR-IR) spectroscopy, ellipsometry, contact angle measurements, and atomic force microscopy (AFM). The thicknesses of the adsorbed monolayers are about 2.8 +/- 0.2 nm for DPPC and 2.0 +/- 0.2 nm for DLPC, as determined by ellipsometry and AFM. Smooth, uniform monolayers of controlled surface density are formed. The surface density of adsorbed layers is comparable to those of close-packed lipid monolayers, as calculated from the ellipsometry and ATR-IR results. Producing controlled-thickness monolayers has applications in boundary lubrication, biomaterials, sensor technologies, and electronics. The method can be used for depositing many biological surfactants or lipids without the need to modify these surfactants chemically to form chemical bonds with the surfaces, as required by the usual chemical SAMs. Moreover, the new method has several advantages compared to the Langmuir-Blodgett (LB) method.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2006

Surface grafting polyethylene glycol (PEG) onto poly(ethylene-co-acrylic acid) films.

Two reaction schemes were developed to covalently graft poly(ethylene glycol) (PEG) chains on poly(ethylene-co-acrylic acid) (EAA) surfaces. The schemes involved surface grafting of linker molecules L-lysine or polypropyleneamine dendrimer (AM64), with subsequent covalent bonding of PEG chains to the linker molecules. NHS and EDC were used to activate the carboxylic acid groups of the EAA in the outermost region of the film, estimated to be 20 nm by ATR-FTIR spectroscopy. XPS demonstrated that the conversion of this activation step was almost 100% in the detected region. After activation, L-lysine or dendrimer was grafted onto the EAA surface, followed by PEG grafting. Combining the data from ATR-FTIR, XPS, and contact angle goniometry, it was found that the PEG chains were grafted on the surface of the EAA film and larger surface coverage was achieved when the dendrimer was used as the intermediate layer. This surface also had the lowest water contact angle.

Journal Article↗
PubMed2006

Structural and water-repellent properties of a urea/poly(dimethylsiloxane) sol-gel hybrid and its bonding to cotton fabric.

A novel diureapropyltriethoxysilane [bis(aminopropyl)-terminated-poly(dimethylsiloxane) (1000)] (PDMSU) sol-gel hybrid was synthesized and applied on cotton to make it water repellent. Surface-energy values of PDMSU deposited on an aluminum substrate were determined, and the contact angle for water was assessed for impregnated cotton fabrics. The stability of the coatings was determined by repetitive washing, and their degradation was investigated with the help of the infrared attenuated total reflection (ATR) technique. The structure of PDMSU was studied by ATR and 29Si NMR spectroscopy. The results showed the active role of the urea groups in PDMSU/cotton interface bonding, but washing led to the relaxation of the urea-urea associations, as inferred from the appearance of a new amide II band at 1541 cm(-1).

Binding Sites↗
PubMed2007

Effect of sequential layer-by-layer surface modifications on the surface energy of plasma-modified poly(dimethylsiloxane).

Surface-initiated grafting of N,N-dimethylacrylamide, styrenesulfonate (SS), and (ar-vinylbenzyl)trimethylammonium chloride (VBTAC) from microwave plasma carboxylated, initiator-functionalized poly(dimethylsiloxane) (PDMS) surfaces was accomplished utilizing reversible addition-fragmentation chain transfer (RAFT) polymerization. Surface spectroscopic attenuated total reflectance (ATR) FT-IR analysis and atomic force microscopy (AFM) measurements were utilized to determine surface grafting and morphological surface features. The VBTAC-grafted PDMS provided a smooth, hydrophilic cationic surface for creating layer-by-layer (LBL) surfaces via alternating deposition of well-defined poly(SS) and poly(VBTAC), also prepared via aqueous RAFT. Comparisons of the ATR FT-IR spectra of the LBL assemblies and those of respective anionic poly(SS) and cationic poly(VBTAC) components confirmed strong electrostatic complexation of a fraction of the sulfonate and quarternary ammonium species in the layers as well as the existence of noncomplexed species. AFM images of surface topology indicated the presence of domains, likely phase-separated segments of the respective homopolymers, as well as interlayer mixing. The employed LBL methodology results in formation of stable, highly hydrophilic surfaces on a PDMS substrate. To our knowledge, this is the first study that illustrates surface functionalization of PDMS using microwave plasma and RAFT polymerization, followed by LBL deposition of polyelectrolytes.

Journal Article↗
PubMed1999

Chemical uptake into human stratum corneum in vivo from volatile and non-volatile solvents.

PURPOSE: Simple, safe and quick in vivo methods for estimating chemical uptake into the stratum corneum (SC) from volatile and non-volatile solvents are invaluable to health risk assessors. This study compares the human in vivo SC uptake of a model compound (4-cyanophenol) from water and acetone using quantitative attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. METHODS: Small areas on the ventral forearms of human volunteers were treated with 4-cyanophenol (CP) dissolved either in water or acetone. After the skin was cleansed of remaining surface CP, SC samples were taken by a standard tape-stripping method. CP concentration profiles across the SC were quantitated by direct measurement of the permeant on the individual tape-strips using ATR-FTIR. RESULTS: Increasing the duration of exposure to CP aqueous solutions resulted in increasing CP uptake into the SC; the kinetics of uptake correlated well with predictive diffusion equations. Increasing the 'dose' of CP in acetone also resulted in increasing uptake into the SC, but uptake eventually plateaued at a maximum level. The amount of CP taken up into the SC from acetone was 2 to 8-fold greater than that from water following similar short-time exposures. CONCLUSIONS: These safe, simple experimental methods provide practical and predictive assessments of chemical uptake into human SC in vivo.

Adult↗
PubMed1990

Percutaneous penetration enhancement in vivo measured by attenuated total reflectance infrared spectroscopy.

A novel application of attenuated total reflectance IR spectroscopy (ATR-IR) was used to monitor the outer several microns of the stratum corneum (SC) and, thereby, demonstrate enhanced percutaneous absorption in vivo in man. 4-Cyanophenol (CP) as a model permeant yielded a unique IR signal, distinct from those of the stratum corneum and the vehicle components. CP was administered for 1, 2, or 3 hr as a 10% (w/v) solution either in propylene glycol or in propylene glycol containing 5% (v/v) oleic acid. The absorbance at 2230 cm-1, which corresponded to C identical to N bond stretching, diminished significantly faster when CP was codelivered with oleic acid. An IR absorbance due primarily to propylene glycol at 1040 cm-1 (C-O stretching) also disappeared more quickly following application of the enhancer-containing solution. In addition, only the formulations with oleic acid induced a higher wavenumber shift in the frequency of the asymmetric C-H bond stretching absorbance. This change indicates increased lipid-chain disorder, the mechanism by which oleic acid is believed to cause enhanced drug transport across the stratum corneum. Therefore, ATR-IR permits one to examine noninvasively the kinetics, extent, and mechanism of percutaneous penetration enhancement in vivo in human subjects.

Adult↗
PubMed1993

The determination of diffusion coefficients in semisolids by Fourier transform infrared (FT-IR) spectroscopy.

A Fourier transform infrared (FT-IR) spectrometer with a horizontal attenuated total reflectance (ATR) cell was used to determine the diffusion coefficients of several liquids in two semisolid materials. The experimental setup was that of a system with one open and one closed boundary wherein the open boundary was maintained at constant concentration. While the liquid of interest was diffusing through the film of ointment, the concentration of liquid at the film surface in contact with the ATR crystal was determined at various times by means of IR absorption measurements. The depth of penetration of the IR radiation into the sample was approximately 0.6-0.9 microns at the wavelengths of analysis. Since the ointment thickness was 157 microns, it was reasonable to assume that only the penetrant reaching the lower boundary was being measured. The values of the diffusion coefficients were then calculated using an equation that appropriately modeled the aforementioned conditions. The liquids tested exhibited diffusion coefficients in anhydrous lanolin and in polyethylene glycol ointment that ranged from 0.56 to 7.2 x 10(-7) and 0.68 to 5.7 x 10(-7) cm2/sec, respectively. The expected molecular weight dependency was observed.

Diffusion↗
PubMed2003

Noninvasive characterization of regional variation in drug transport into human stratum corneum in vivo.

PURPOSE: To investigate the mechanisms underlying the regional variations in drug transport into human stratum corneum (SC) of two model compounds of different lipophilicity and molecular size, 4-cyanophenol (CP) and cimetidine (CM), in vivo by non-invasive, quantitative attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. METHODS: Saturated solutions of CP and CM were applied to the skin surface of eleven Chinese men, at five anatomical sites, including forearm, back, thigh, leg, and abdomen, for 10-15 min and 3-5 h, respectively. After the skin surface was cleansed of remaining chemicals, the SC was tape-stripped sequentially up to 20 times, and the drug concentration profiles in the tape-stripped SC were determined using ATR-FTIR spectroscopy. Thickness of the SC was estimated simultaneously using two-point measurements of transepidermal water loss before and after completion of tape stripping. Estimation of partition, diffusion, and permeability coefficients was achieved by analysis of the data using the unsteady-state diffusion equation. RESULTS: The rank orders of regional variation in partition and diffusion coefficients of CP and CM were different. The rank order of regional variation in permeability coefficients was similar for both drugs and decreased in the order of back > forearm > thigh > leg > or = abdomen, but the variation was more prominent for CM. CONCLUSIONS: Regional variation in SC transport of CP was mainly influenced by its intrinsic diffusivity across the SC, whereas variation in transport of CM could be attributed to both thermodynamic and kinetic differences among different anatomical skin sites.

Administration, Cutaneous↗
PubMed2003

Effects of sucrose oleate and sucrose laureate on in vivo human stratum corneum permeability.

PURPOSE: The purpose of this work was to 1) investigate the effect of sucrose esters (sucrose oleate and sucrose laureate in water or in Transcutol, TC) on the stratum corneum (SC) barrier properties in vivo and 2) examine the impact of these surfactant-like molecules on the in vivo percutaneous penetration of a model penetrant 4-hydroxybenzonitrile (4-HB). METHODS: Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and transepidermal water loss measurements were used to evaluate the sucrose oleate- and sucrose laureate-induced biophysical changes in SC barrier function in vivo. In addition. the effect of the enhancers on 4-HB penetration was monitored in vivo using ATR-FTIR spectroscopy in conjunction with tape-stripping of the treated site. RESULTS: Treatment of the skin with 2% sucrose laureate or sucrose oleate in TC significantly increased the extent of 4-HB penetration relative to the control. Furthermore, when skin treated with these formulations was examined spectroscopically, the C-H asymmetric and symmetric stretching bands of the lipid methylene groups were characterized by 1) decreased absorbances and 2) frequency shifts to higher wavenumbers. These effects on the SC lipids and 4-HB penetration were more pronounced for sucrose laureate when combined with TC. CONCLUSIONS: A combination of sucrose esters (oleate or laureate) and TC is able to temporally alter the stratum corneum barrier properties, thereby promoting 4-HB penetration. These molecules are worthy of further investigation as potential candidates for inclusion in transdermal formulations as penetration enhancers.

Adult↗
PubMed2002

Calf muscle function after Achilles tendon rupture. A prospective, randomised study comparing surgical and non-surgical treatment.

In a prospective, randomised, multicentre study, 112 patients with Achilles tendon rupture (ATR) were allocated to surgical treatment (n=59), followed by early functional rehabilitation using a brace, and non-surgical treatment (n=53), i.e. eight weeks of plaster treatment. In this study, the results of the isokinetic muscle strength evaluation are presented for contractions in both the concentric and the eccentric mode, plantar flexion and dorsiflexion, two angular velocities and three different positions of the subject. The heel-raise test for endurance, maximum calf circumference and tendon width were also evaluated. The re-rupture rate was 20.8% in the non-surgically-treated group and 1.7% in the surgically-treated group. No significant differences were found between the treatment groups in terms of the isokinetic strength measurements and the endurance test among the patients who did not sustain a re-rupture. If a re-rupture is avoided, both surgical and non-surgical treatment for ATR produce good functional outcome; however, the muscle function was not restored after two years in either group.

Achilles Tendon↗
PubMed1990

Effect of bleached rhodopsin on signal amplification in rod visual receptors.

Bleaching of rhodopsin markedly desensitizes the vertebrate visual system during a subsequent period of dark adaptation. Previous studies have indicated an origin of bleaching desensitization in the visual pigment itself, but have not identified the mechanism of action. A candidate for the site at which densensitization is initially expressed is the activation of transducin (formation of T*) on the rod disk membranes; this reaction directly involves rhodopsin in its photoactivated (R*) form and mediates initial amplification of the visual signal (reviewed in refs 7-9). We have analysed the effect of bleaching on the sensitivity of a flash-induced light-scattering signal known to monitor the disk-based amplifier, and which has been established as specifically monitoring transducin activation. We have recorded this signal from functioning retinal rods in situ ('ATR' signal) and find that bleaches inducing a pronounced, sustained loss in rod electrophysiological sensitivity do not alter the sensitivity of the ATR response after correction for reduced quantum catch. Our results indicate that the biochemical gain of the R*----T* transduction stage remains unchanged in the presence of bleached pigment and implicate a subsequent reaction as the first to show a sustained, bleaching-dependent gain reduction.

Animals↗
PubMed1997

Variation in astigmatism following the single-step, self-sealing clear corneal section for phacoemulsification.

PURPOSE: A single-step, self-sealing, 3.2 mm clear corneal section is described and the incidence and variation of surgically induced astigmatism following phacoemulsification over a period of 3 months is determined. METHODS: Twenty-two patients who underwent uncomplicated 3.2 mm clear corneal phacoemulsification with foldable Allergan silicone intraocular lens implantation were autorefracted pre-operatively and on day 1, week 1, week 6 and at 3 months. The variation in induced astigmatism was analysed using the subtraction method and vector analysis. The change in direction of the cylindrical axis was examined. RESULTS: The induced astigmatism represented by the total vector on day 1 was 1.17 D and vector decomposition ratio, ATR:WTR (against-the-rule:with-the-rule), was 21.05:78.95. The total vector increased by 0.5 D in the first week and then stabilised. Vector decomposition showed an against-the-rule astigmatic drift so that by 3 months the ATR:WTR was 40.49:59.91. There was a tendency of the axis of the negative cylinder to swing towards the corneal section meridian on day 1 and to oscillate around that meridian at week 1 and week 6. By 3 months the direction reverted to that pre-operatively, in most cases. CONCLUSIONS: The single-step, self-sealing clear corneal section is mechanically stable and, though there is some variability in the measured astigmatism, there is an acceptable functional result throughout the post-operative period.

Aged↗
PubMed1996

Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy.

Since the renin angiotensin system (RAS) is established as an important factor in renal disease progression, we determined whether RAS alleles that have been linked to variability in outcome in several cardiovascular diseases also affect progression of IgA nephropathy. These genetic variants include: (1) angiotensin I converting enzyme deletion polymorphism in intron 16 (ACE I/D), reported to be associated with increased risk of myocardial infarction as well as left ventricular hypertrophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), reported to be associated with hypertension in Caucasians; and (3) an angiotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) which shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR amplification of genomic DNA samples from 64 Caucasian patients in the USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal status was followed for an average of almost seven years. Patients who presented with and maintained normal serum creatinine (Cr, < 1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, in patients with progression (initially normal Cr increased to a mean of 4.5 +/- 0.86 mg/dl), ACE genotype frequencies were II:22%, ID:44%, DD:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The association of the DD genotype with progression was even more striking when patients with other risk factors (hypertension and/or heavy proteinuria) were excluded. In this subgroup, the genotype frequencies in patients with stable creatinine versus those with deterioration in renal function was 53%, 47%, and 0% versus 0%, 40%, and 60%, respectively, for II, ID, and DD genotypes (P = 0.009 by Fisher's exact test, progressors vs. non-progressors). Further, sequence analysis of the I gene polymorphism revealed a potential 13 bp silence motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, these results indicate that, although polymorphism in each of the three genes in the RAS system has been linked to cardiovascular diseases, only the ACE I/D polymorphism is associated with progressive deterioration in renal function in IgA nephropathy. Since previous observations link ACE polymorphism with ACE activity, these findings imply a widespread importance of ACE in modulating destructive processes in different organs.

Alleles↗
PubMed2005

The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor.

Some stimulatory receptors of the innate immune system, such as the NKG2D receptor (also called KLRK1) expressed by natural killer cells and activated CD8(+)T cells, recognize self-molecules that are upregulated in diseased cells by poorly understood mechanisms. Here we show that mouse and human NKG2D ligands are upregulated in non-tumour cell lines by genotoxic stress and stalled DNA replication, conditions known to activate a major DNA damage checkpoint pathway initiated by ATM (ataxia telangiectasia, mutated) or ATR (ATM- and Rad3-related) protein kinases. Ligand upregulation was prevented by pharmacological or genetic inhibition of ATR, ATM or Chk1 (a downstream transducer kinase in the pathway). Furthermore, constitutive ligand expression by a tumour cell line was inhibited by targeting short interfering RNA to ATM, suggesting that ligand expression in established tumour cells, which often harbour genomic irregularities, may be due to chronic activation of the DNA damage response pathway. Thus, the DNA damage response, previously shown to arrest the cell cycle and enhance DNA repair functions, or to trigger apoptosis, may also participate in alerting the immune system to the presence of potentially dangerous cells.

Animals↗
PubMed2004

PML regulates p53 stability by sequestering Mdm2 to the nucleolus.

The promyelocytic leukaemia (PML) tumour-suppressor protein potentiates p53 function by regulating post-translational modifications, such as CBP-dependent acetylation and Chk2-dependent phosphorylation, in the PML-Nuclear Body (NB). PML was recently shown to interact with the p53 ubiquitin-ligase Mdm2 (refs 4-6); however, the mechanism by which PML regulates Mdm2 remains unclear. Here, we show that PML enhances p53 stability by sequestering Mdm2 to the nucleolus. We found that after DNA damage, PML and Mdm2 accumulate in the nucleolus in an Arf-independent manner. In addition, we found that the nucleolar localization of PML is dependent on ATR activation and phosphorylation of PML by ATR. Notably, in Pml(-/-) cells, sequestration of Mdm2 to the nucleolus was impaired, as well as p53 stabilization and the induction of apoptosis. Furthermore, we demonstrate that PML physically associates with the nucleolar protein L11, and that L11 knockdown impairs the ability of PML to localize to nucleoli after DNA damage. These findings demonstrate an unexpected role of PML in the nucleolar network for tumour suppression.

ADP-Ribosylation Factor 1↗