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1.
Artigo em Inglês | MEDLINE | ID: mdl-32740538

RESUMO

OBJECTIVES: Crohn disease (CD) can affect patient's quality of life (QOL) with physical, social, and psychological impacts. This study aimed to investigate the QOL of children with CD and its relationship with patient and disease characteristics. METHODS: Children ages from 10 to 17 years with diagnosed CD for more than 6 months were eligible to this cross-sectional study conducted in 35 French pediatric centers. QOL was assessed by the IMPACT-III questionnaire. Patient and disease characteristics were collected. RESULTS: A total of 218 children (42% of girls) were included at a median age of 14 years (interquartile range [IQR]: 13--16). Median duration of CD was 3.2 years (IQR: 1.7-5.1) and 63% of children were in clinical remission assessed by wPCDAI. Total IMPACT-III score was 62.8 (±11.0). The lowest score was in "emotional functioning" subdomain (mean: 42.8 ±â€Š11.2). Clinical remission was the main independent factor associated with QOL of children with CD (5.74 points higher compared with those "with active disease", 95% confidence interval [CI] 2.77--8.70, P < 0.001). Age of patient at the evaluation was found negatively correlated with QOL (-0.76 per year, 95% CI: -1.47 to -0.06, P = 0.009). Presence of psychological disorders was associated with a lower QOL (-9.6 points lower to those without, 95% CI: -13.34 to -5.86, P < 0.0001). Total IMPACT-III and its subdomains scores were not related to sex, disease duration, or treatments. CONCLUSIONS: These results not only confirm that clinical remission is a major issue for the QOL of patients, but also highlights the importance of psychological care.

2.
EMBO J ; 33(16): 1784-801, 2014 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-24975362

RESUMO

Mitogen-activated protein kinases (MAPKs) are highly conserved protein kinase modules, and they control fundamental cellular processes. While the activation of MAPKs has been well studied, little is known on the mechanisms driving their inactivation. Here we uncover a role for ubiquitination in the inactivation of a MAPK module. Extracellular-signal-regulated kinase 5 (ERK5) is a unique, conserved member of the MAPK family and is activated in response to various stimuli through a three-tier cascade constituting MEK5 and MEKK2/3. We reveal an unexpected role for Inhibitors of Apoptosis Proteins (IAPs) in the inactivation of ERK5 pathway in a bimodal manner involving direct interaction and ubiquitination. XIAP directly interacts with MEKK2/3 and competes with PB1 domain-mediated binding to MEK5. XIAP and cIAP1 conjugate predominantly K63-linked ubiquitin chains to MEKK2 and MEKK3 which directly impede MEK5-ERK5 interaction in a trimeric complex leading to ERK5 inactivation. Consistently, loss of XIAP or cIAP1 by various strategies leads to hyperactivation of ERK5 in normal and tumorigenic cells. Loss of XIAP promotes differentiation of human primary skeletal myoblasts to myocytes in a MEKK2/3-ERK5-dependent manner. Our results reveal a novel, obligatory role for IAPs and ubiquitination in the physical and functional disassembly of ERK5-MAPK module and human muscle cell differentiation.


Assuntos
Proteínas Inibidoras de Apoptose/metabolismo , MAP Quinase Quinase 5/metabolismo , MAP Quinase Quinase Quinase 3/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Ubiquitina/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Diferenciação Celular , Células Cultivadas , Proteínas de Ligação a DNA , Ativação Enzimática , Humanos , Proteínas Inibidoras de Apoptose/genética , MAP Quinase Quinase 5/genética , MAP Quinase Quinase Quinase 2 , MAP Quinase Quinase Quinase 3/genética , MAP Quinase Quinase Quinases/genética , Fatores de Transcrição MEF2/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/genética , Mioblastos/citologia , Mioblastos/metabolismo , Proteínas Nucleares/metabolismo , Multimerização Proteica , Estrutura Terciária de Proteína , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Ubiquitinação , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
3.
EMBO J ; 31(11): 2615-28, 2012 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-22531785

RESUMO

Bacterial pathogens modulate host cell apoptosis to establish a successful infection. Pore-forming toxins (PFTs) secreted by pathogenic bacteria are major virulence factors and have been shown to induce various forms of cell death in infected cells. Here we demonstrate that the highly conserved caspase-2 is required for PFT-mediated apoptosis. Despite being the second mammalian caspase to be identified, the role of caspase-2 during apoptosis remains enigmatic. We show that caspase-2 functions as an initiator caspase during Staphylococcus aureus α-toxin- and Aeromonas aerolysin-mediated apoptosis in epithelial cells. Downregulation of caspase-2 leads to a strong inhibition of PFT-mediated apoptosis. Activation of caspase-2 is PIDDosome-independent, and endogenous caspase-2 is recruited to a high-molecular-weight complex in α-toxin-treated cells. Interestingly, prevention of PFT-induced potassium efflux inhibits the formation of caspase-2 complex, leading to its inactivation, thus resisting apoptosis. These results revealed a thus far unknown, obligatory role for caspase-2 as an initiator caspase during PFT-mediated apoptosis.


Assuntos
Apoptose/fisiologia , Caspase 2/metabolismo , Cisteína Endopeptidases/metabolismo , Apoptose/efeitos dos fármacos , Toxinas Bacterianas/farmacologia , Regulação para Baixo , Células HeLa , Proteínas Hemolisinas/farmacologia , Humanos , Queratinócitos/metabolismo , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Potássio/análise , Potássio/metabolismo
4.
J Biol Chem ; 282(44): 31928-36, 2007 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-17804416

RESUMO

The putative selectivity filter of the epithelial sodium channel (ENaC) comprises a three-residue sequence G/SXS, but it remains uncertain whether the backbone atoms of this sequence or whether their side chains are lining the pore. It has been reported that the S589C mutation in the selectivity filter of alphaENaC renders the channel sensitive to block by externally applied Cd2+; this was interpreted as evidence for Cd2+ coordination with the thiol group of the side chain of alpha589C, pointing toward the pore lumen. Because the alphaS589C mutation alters the monovalent to divalent cation selectivity ratio of ENaC and because internally applied Cd2+ blocks wild-type ENaC with high affinity, we hypothesized that the inhibition of alphaS589C ENaC by Cd2+ results rather from the coordination of this cation with native cysteine residues located in the internal pore of ENaC. We show here that Cd2+ inhibits not only ENaC alphaS589C and alphaS589D but also alphaS589N mutants and that Ca2+ weakly interacts with the S589D mutant. The block of alphaS589C, -D, and -N mutants is characterized by a slow on-rate, is nearly irreversible, is voltage-dependent, and can be prevented by amiloride. The C546S mutation in the second transmembrane helix of gamma subunit in the background of the ENaC alphaS589C, -D, or -N mutants reduces the sensitivity to block by Cd2+ and renders the block rapidly reversible. We conclude therefore that the block by Cd2+ of the alphaS589C, -D, and -N mutants results from the trapping of Cd2+ ions in the internal pore of the channel and involves Cys-546 in the second transmembrane helix of the gammaENaC subunit.


Assuntos
Cádmio/farmacologia , Bloqueadores do Canal de Sódio Epitelial , Proteínas de Xenopus/antagonistas & inibidores , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Canais Epiteliais de Sódio/química , Canais Epiteliais de Sódio/genética , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Oócitos , Estrutura Secundária de Proteína , Alinhamento de Sequência , Proteínas de Xenopus/química , Proteínas de Xenopus/genética , Xenopus laevis
5.
Mol Pharmacol ; 71(2): 473-82, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17105867

RESUMO

Aldosterone binds to the mineralocorticoid receptor (MR) and exerts fine control over Na+ absorption in renal collecting duct cells (CCDs). Many natural and synthetic steroids can also bind to the MR to produce agonist or antagonist effects. Here, we investigate whether androgenic hormones act as MR agonist or antagonist ligands in CCDs. Testosterone (T), dihydrotestosterone (DHT), and methyltrienolone (R1881), a synthetic androgen agonist, all bind to the MR. R1881 displayed the same affinity for MR as aldosterone. Androgens did not activate the MR transiently expressed in human embryonic kidney 293T cells but did antagonize aldosterone-induced MR trans-activation activity (R1881>DHT>T). Short-circuit current (Isc) experiments, used to measure transepithelial Na+ transport, revealed that 10(-5) M T and DHT or R1881 prevented the increase in the amiloride-sensitive component of Isc caused by aldosterone in mouse mpkCCDcl4 collecting duct cells partially and totally, respectively. In contrast, androgens had no effect on stimulated Isc elicited by the specific glucocorticoid agonist 11beta,17beta-dihydroxy-17alpha-(1-propynyl) and rost-1,4,6-trien-3-one (RU26988). Docking of steroids within the crystal structure of the ligand-binding domain of MR, together with trans-activation studies, revealed that the contacts between the 17beta-hydroxyl group of androgens and the Asn770, Cys942, and Thr945 residues of the ligand-binding cavity stabilize ligand binding complexes but are not strong enough to keep the receptor in its active state. Altogether, these findings indicate that androgen ligands, particularly R1881, act as MR antagonists in aldosterone target cells and provide new insights into the requirements for MR activation to occur and for the designing of new selective MR antagonists.


Assuntos
Metribolona/farmacologia , Antagonistas de Receptores de Mineralocorticoides , Androgênios/farmacologia , Animais , Sítios de Ligação , Linhagem Celular , Eletrofisiologia , Humanos , Rim/citologia , Ligantes , Camundongos , Sódio/metabolismo , Congêneres da Testosterona/farmacologia
6.
J Biol Chem ; 281(17): 11787-91, 2006 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-16497675

RESUMO

Using a substituted cysteine accessibility scan, we have investigated the structures that form the internal pore of the acid-sensing ion channel 1a. We have identified the amino acid residues Ala-22, Ile-33, and Phe-34 in the amino terminus and Arg-43 in the first transmembrane helix, which when mutated into cysteine, were modified by intracellular application of MTSET, resulting in channel inhibition. The inhibition of the R43C mutant by internal MTSET requires opening of the channel. In addition, binding of Cd2+ ions to R43C slows the channel inactivation. This indicates that the first transmembrane helix undergoes conformational changes during channel inactivation. The effect of Cd2+ on R43C can be obtained with Cd2+ applied at either the extracellular or the intracellular side, indicating that R43C is located in the channel pore. The block of the A22C, I33C, and F34C mutants by MTSET suggests that these residues in the amino terminus of the channel also participate to the internal pore.


Assuntos
Cisteína/metabolismo , Ativação do Canal Iônico/fisiologia , Proteínas de Membrana , Mutação/genética , Proteínas do Tecido Nervoso , Canais de Sódio , Canais Iônicos Sensíveis a Ácido , Animais , Cádmio/metabolismo , Cisteína/química , Cisteína/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microinjeções , Mutagênese Sítio-Dirigida , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Oócitos/metabolismo , Técnicas de Patch-Clamp , Conformação Proteica , Canais de Sódio/genética , Canais de Sódio/metabolismo , Xenopus laevis/metabolismo
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