RESUMEN
The actin cytoskeleton impacts practically every function of a eukaryotic cell. Historically, the best-characterized cytoskeletal activities are in cell morphogenesis, motility, and division. The structural and dynamic properties of the actin cytoskeleton are also crucial for establishing, maintaining, and changing the organization of membrane-bound organelles and other intracellular structures. Such activities are important in nearly all animal cells and tissues, although distinct anatomical regions and physiological systems rely on different regulatory factors. Recent work indicates that the Arp2/3 complex, a broadly expressed actin nucleator, drives actin assembly during several intracellular stress response pathways. These newly described Arp2/3-mediated cytoskeletal rearrangements are coordinated by members of the Wiskott-Aldrich Syndrome Protein (WASP) family of actin nucleation-promoting factors. Thus, the Arp2/3 complex and WASP-family proteins are emerging as crucial players in cytoplasmic and nuclear activities including autophagy, apoptosis, chromatin dynamics, and DNA repair. Characterizations of the functions of the actin assembly machinery in such stress response mechanisms are advancing our understanding of both normal and pathogenic processes, and hold great promise for providing insights into organismal development and interventions for disease.
Asunto(s)
Actinas , Familia de Proteínas del Síndrome de Wiskott-Aldrich , Animales , Familia de Proteínas del Síndrome de Wiskott-Aldrich/metabolismo , Actinas/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Citoesqueleto de Actina/metabolismo , Citoesqueleto/metabolismo , Proteína del Síndrome de Wiskott-Aldrich/genética , Proteína del Síndrome de Wiskott-Aldrich/metabolismo , Proteína 3 Relacionada con la Actina/metabolismoRESUMEN
The actin cytoskeleton is a ubiquitous participant in cellular functions that maintain viability, but how it controls programmed cell death is not well understood. Here we show that in response to DNA damage, human cells form a juxtanuclear F-actin-rich territory that coordinates the organized progression of apoptosome assembly to caspase activation. This cytoskeletal compartment is created by the actin nucleation factors JMY, WHAMM, and the Arp2/3 complex, and it excludes proteins that inhibit JMY and WHAMM activity. Within the territory, mitochondria undergo outer membrane permeabilization and JMY localization overlaps with punctate structures containing the core apoptosome components cytochrome c and Apaf-1. The F-actin-rich area also encompasses initiator caspase-9 and clusters of a cleaved form of executioner caspase-3 but restricts accessibility of the caspase inhibitor XIAP. The clustering and potency of caspase-3 activation are positively regulated by the amount of actin polymerized by JMY and WHAMM. These results indicate that JMY-mediated actin reorganization functions in apoptotic signaling by coupling the biogenesis of apoptosomes to the localized processing of caspases.
Asunto(s)
Actinas , Apoptosomas , Humanos , Actinas/metabolismo , Caspasa 3 , Apoptosomas/metabolismo , Apoptosis/fisiología , Caspasas/metabolismo , Citoesqueleto de Actina/metabolismo , Daño del ADN , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a MicrotúbulosRESUMEN
The actin cytoskeleton is a well-known player in most vital cellular processes, but comparably little is understood about how the actin assembly machinery impacts programmed cell death pathways. In the current study, we explored roles for the human Wiskott-Aldrich Syndrome Protein (WASP) family of actin nucleation factors in DNA damage-induced apoptosis. Inactivation of each WASP-family gene revealed that two of them, JMY and WHAMM, are necessary for rapid apoptotic responses. JMY and WHAMM participate in a p53-dependent cell death pathway by enhancing mitochondrial permeabilization, initiator caspase cleavage, and executioner caspase activation. JMY-mediated apoptosis requires actin nucleation via the Arp2/3 complex, and actin filaments are assembled in cytoplasmic territories containing clusters of cytochrome c and active caspase-3. The loss of JMY additionally results in significant changes in gene expression, including upregulation of the WHAMM-interacting G-protein RhoD. Depletion or deletion of RHOD increases cell death, suggesting that RhoD normally contributes to cell survival. These results give rise to a model in which JMY and WHAMM promote intrinsic cell death responses that can be opposed by RhoD.
Asunto(s)
Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Nucleares/genética , Transactivadores/genética , Proteína p53 Supresora de Tumor/genética , Síndrome de Wiskott-Aldrich/genética , Proteínas de Unión al GTP rho/genética , Citoesqueleto de Actina/genética , Proteína 2 Relacionada con la Actina/genética , Complejo 2-3 Proteico Relacionado con la Actina/genética , Proteína 3 Relacionada con la Actina/genética , Apoptosis/genética , Citocromos c/genética , Daño del ADN/genética , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , ARN Interferente Pequeño/genética , Proteína del Síndrome de Wiskott-Aldrich/genéticaRESUMEN
Fibromyalgia (FM) patients were recently found to have more symptom burden from bothersome pelvic pain syndromes that women seeking care for pelvic floor disease at a urogynecology clinic. We sought to further characterize pelvic floor symptoms in a larger sample of FM patients using of validated questionnaires. Female listserv members of the Fibromyalgia Information Foundation completed an online survey of three validated questionnaires: the Pelvic Floor Distress Inventory 20 (PFDI-20), the Pelvic Pain, Urgency and Frequency Questionnaire (PUF), and the Revised Fibromyalgia Impact Questionnaire (FIQR). Scores were characterized using descriptive statistics. Patients (n = 204 with complete data on 177) were on average 52.3 ± 11.4 years with a mean parity of 2.5 ± 1.9. FM severity based on FIQR score (57.2 ± 14.9) positively correlated with PFDI-20 total 159.08 ± 55.2 (r = .34, p < .001) and PUF total 16.54 ± 7 (r = .36, p < .001). Women with FM report significantly bothersome pelvic floor and urinary symptoms. Fibromyalgia management should include evaluation and treatment of pelvic floor disorders recognizing that pelvic distress and urinary symptoms are associated with more severe FM symptoms. Validated questionnaires, like the ones used in this study, are easily incorporated into clinical practice.
Asunto(s)
Fibromialgia/complicaciones , Trastornos del Suelo Pélvico/complicaciones , Trastornos Urinarios/complicaciones , Adulto , Estudios Transversales , Femenino , Humanos , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To evaluate whether antepartum pelvic floor muscle strength, as measured by the Brink scale, predicts postpartum anal incontinence. STUDY DESIGN: This prospective cohort study of primigravid women used validated questionnaires and standardized pelvic examinations to evaluate subjects during the third trimester and at 2 postpartum time points. RESULTS: Of the initial 129 subjects, 102 and 81 completed 2 week and 6 month postpartum visits. 35% had cesarean deliveries. The antepartum prevalence of fecal incontinence (14%) did not differ significantly from the postpartum (17% at 2 weeks, 11% at 6 months). However, the prevalence of flatal incontinence fell from antepartum (65%) to postpartum (47% at 2 weeks, P = .001; 49% at 6 months, P = .012). Mean Brink score decreased postpartum; no correlations were found between Brink score and questionnaire scores. CONCLUSION: Anal incontinence symptoms are common in the third trimester of a first pregnancy and may regress or resolve after delivery. Brink score did not predict postpartum anal incontinence.
Asunto(s)
Incontinencia Fecal/fisiopatología , Diafragma Pélvico/fisiopatología , Periodo Posparto , Valor Predictivo de las Pruebas , Trastornos Puerperales/fisiopatología , Adulto , Femenino , Humanos , Embarazo , Complicaciones del Embarazo/fisiopatología , Tercer Trimestre del Embarazo , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
OBJECTIVE: The objective of the study was to compare apical support anatomic outcomes following vaginal mesh procedure (VMP) (Prolift) to uterosacral ligament suspension (USLS) and abdominal sacrocolpopexy (ASC). STUDY DESIGN: This multicenter, retrospective chart review compared apical anatomic success (stage 0 or 1 based on point C or D of the Pelvic Organ Prolapse Quantification), level of vaginal apex (point C or D) 3-6 months after prolapse repair at 10 US centers between 2004 and 2007. RESULTS: VMP, USLS, and ASC were performed for 206, 231, and 305 subjects respectively. There was no difference in apical success after VMP (98.8%) compared with USLS (99.1%) or ASC (99.3%) (both P = 1.00) 3-6 months after surgery. The average elevation of the vaginal apex was lower after VMP (-6.9 cm) than USLS (-8.05 cm) and ASC (-8.5 cm) (both P < .001) CONCLUSION: Patients undergoing VMP have similar apical success compared with USLS and ASC despite lower vaginal apex 3-6 month after surgery.