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1.
J Pathol ; 233(3): 247-57, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24604753

RESUMEN

Most patients with tuberous sclerosis complex (TSC) develop cortical tubers that cause severe neurological disabilities. It has been suggested that defects in neuronal differentiation and/or migration underlie the appearance of tubers. However, the precise molecular alterations remain largely unknown. Here, by combining cytological and immunohistochemical analyses of tubers from nine TSC patients (four of them diagnosed with TSC2 germline mutations), we show that alteration of microtubule biology through ROCK2 signalling contributes to TSC neuropathology. All tubers showed a larger number of binucleated neurons than expected relative to control cortex. An excess of normal and altered cytokinetic figures was also commonly observed. Analysis of centrosomal markers suggested increased microtubule nucleation capacity, which was supported by the analysis of an expression dataset from cortical tubers and control cortex, and subsequently linked to under-expression of Rho-associated coiled-coil containing kinase 2 (ROCK2). Thus, augmented microtubule nucleation capacity was observed in mouse embryonic fibroblasts and human fibroblasts deficient in the Tsc2/TSC2 gene product, tuberin. Consistent with ROCK2 under-expression, microtubule acetylation was found to be increased with tuberin deficiency; this alteration was abrogated by rapamycin treatment and mimicked by HDAC6 inhibition. Together, the results of this study support the hypothesis that loss of TSC2 expression can alter microtubule organization and dynamics, which, in turn, deregulate cell division and potentially impair neuronal differentiation.


Asunto(s)
Corteza Cerebral/enzimología , Microtúbulos/enzimología , Neuronas/enzimología , Transducción de Señal , Esclerosis Tuberosa/enzimología , Quinasas Asociadas a rho/metabolismo , Animales , Estudios de Casos y Controles , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Citocinesis , Fibroblastos/enzimología , Fibroblastos/patología , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Microtúbulos/efectos de los fármacos , Microtúbulos/patología , Complejos Multiproteicos/antagonistas & inhibidores , Complejos Multiproteicos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis , Neuronas/efectos de los fármacos , Neuronas/patología , Fenotipo , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Transfección , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patología , Proteína 2 del Complejo de la Esclerosis Tuberosa , Tubulina (Proteína)/metabolismo , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genética , Quinasas Asociadas a rho/genética
2.
Breast Cancer Res ; 16(3): R53, 2014 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-24886537

RESUMEN

INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process. METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression. RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy. CONCLUSIONS: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Receptor alfa de Estrógeno/metabolismo , Indazoles/farmacología , Proteínas Proto-Oncogénicas c-vav/genética , Androstadienos/uso terapéutico , Antineoplásicos Hormonales/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Biomarcadores de Tumor/genética , Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Activadores de Enzimas/farmacología , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Variación Genética , Humanos , Letrozol , Células MCF-7 , Nitrilos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Interferencia de ARN , ARN Interferente Pequeño , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Toremifeno/farmacología , Toremifeno/uso terapéutico , Triazoles/uso terapéutico
3.
PLoS Biol ; 9(11): e1001199, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22110403

RESUMEN

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.


Asunto(s)
Proteína BRCA1/metabolismo , Neoplasias de la Mama/metabolismo , Polaridad Celular , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Aurora Quinasa A , Aurora Quinasas , Proteína BRCA1/genética , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Mama/citología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Polaridad Celular/genética , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Células HeLa , Heterocigoto , Humanos , Microtúbulos/fisiología , Microtúbulos/ultraestructura , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Estrógenos/análisis
4.
Br J Ophthalmol ; 108(2): 253-262, 2024 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-36627173

RESUMEN

AIM: To explore associations between artificial intelligence (AI)-based fluid compartment quantifications and 12 months visual outcomes in OCT images from a real-world, multicentre, national cohort of naïve neovascular age-related macular degeneration (nAMD) treated eyes. METHODS: Demographics, visual acuity (VA), drug and number of injections data were collected using a validated web-based tool. Fluid compartment quantifications including intraretinal fluid (IRF), subretinal fluid (SRF) and pigment epithelial detachment (PED) in the fovea (1 mm), parafovea (3 mm) and perifovea (6 mm) were measured in nanoliters (nL) using a validated AI-tool. RESULTS: 452 naïve nAMD eyes presented a mean VA gain of +5.5 letters with a median of 7 injections over 12 months. Baseline foveal IRF associated poorer baseline (44.7 vs 63.4 letters) and final VA (52.1 vs 69.1), SRF better final VA (67.1 vs 59.0) and greater VA gains (+7.1 vs +1.9), and PED poorer baseline (48.8 vs 57.3) and final VA (55.1 vs 64.1). Predicted VA gains were greater for foveal SRF (+6.2 vs +0.6), parafoveal SRF (+6.9 vs +1.3), perifoveal SRF (+6.2 vs -0.1) and parafoveal IRF (+7.4 vs +3.6, all p<0.05). Fluid dynamics analysis revealed the greatest relative volume reduction for foveal SRF (-16.4 nL, -86.8%), followed by IRF (-17.2 nL, -84.7%) and PED (-19.1 nL, -28.6%). Subgroup analysis showed greater reductions in eyes with higher number of injections. CONCLUSION: This real-world study describes an AI-based analysis of fluid dynamics and defines baseline OCT-based patient profiles that associate 12-month visual outcomes in a large cohort of treated naïve nAMD eyes nationwide.


Asunto(s)
Mácula Lútea , Degeneración Macular , Desprendimiento de Retina , Degeneración Macular Húmeda , Humanos , Ranibizumab/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Factor A de Crecimiento Endotelial Vascular , Inteligencia Artificial , Tomografía de Coherencia Óptica , Inyecciones Intravítreas , Desprendimiento de Retina/tratamiento farmacológico , Degeneración Macular/tratamiento farmacológico , Líquido Subretiniano , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológico
5.
Ophthalmol Ther ; 12(5): 2537-2555, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37400599

RESUMEN

INTRODUCTION: Timely anti-vascular endothelial growth factor (VEGF) treatment is crucial for visual function in neovascular age-related macular degeneration (nAMD). The aim of this study was to assess the reasons for anti-VEGF treatment delay during the COVID-19 lockdown and its clinical impact in patients with nAMD. METHODS: A retrospective, observational, multicentre study in patients with nAMD treated with anti-VEGF therapy was performed in 16 centres nationwide. Data were retrieved from the FRB Spain registry, patient medical records and administrative databases. Patients were divided into two groups based on whether they received or missed intravitreal injections during the COVID-19 lockdown. RESULTS: A total of 302 eyes from 245 patients were included (timely treated group [TTG] 126 eyes; delayed treatment group [DTG] 176 eyes). Visual acuity (VA; ETDRS letters) decreased from baseline to post-lockdown visit in the DTG (mean [standard deviation] 59.1 (20.8) vs. 57.1 (19.7); p = 0.020) and was maintained in the TTG (64.2 [16.5] vs. 63.6 [17.5]; p = 0.806). VA worsened by an average of - 2.0 letters in the DTG and by - 0.6 in the TTG (p = 0.016). A higher proportion of visits were cancelled due to hospital overload in the TTG (76.5%) than in the DTG (47%), and a higher proportion of patients missed visits in the DTG (53%) than in the TTG (23.5%, p = 0.021), with fear of COVID-19 infection being the main reason for missed visits (60%/50%). CONCLUSIONS: Treatment delays were caused by both hospital saturation and patients' decision; the latter being mainly driven by fear of COVID-19 infection. These delays had a detrimental effect on the visual outcomes in nAMD patients.

6.
Eur J Ophthalmol ; 32(1): 385-394, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33719641

RESUMEN

BACKGROUND/AIMS: The present study evaluates the burden of neovascular age-related macular degeneration (nAMD) to Healthcare System and patients, describing the management and treatment effectiveness in routine clinical practice in Spain. METHODS: Observational, non-interventional, cross-sectional, retrospective (24 months), multicentre study including patients who started treatment with licensed vascular endothelial growth factor inhibitors (anti-VEGF) for nAMD with a minimum follow up of 24 months. RESULTS: 126 evaluable patients were included with mean (SD) age of 79.1 (7.5) years. From diagnosis, it took a mean (SD) of 0.5 (0.5) months for the first treatment. Throughout 24 months, mean (SD) number of visits per patient was 16.0 (5.0), 9.4 (4.3) associated intravitreal injection. There were 1186 injection visits, 53.6% of them only with injection and 46.3% with injection and tests. After loading phase, preferred treatment regimens were T&E (46.0%), PRN (44.4%), fixed regimen (4.0%), and others (5.6%). Total number of visits in patients with T&E and PRN were 16.5 (5.7) and 15.5 (4.7), respectively. After complete loading phase, mean (SD) time between two consecutive treatment injections was 2.2 (1.6) months. 27.8% patients underwent a treatment change, being lack of response the most frequent reason to change (43.2%). Mean (SD) best-corrected visual acuity change was 2.1 (15.9) letters at 24 months. CONCLUSION: This study showed an important burden to Healthcare System and patients related to monitoring visits. More efficacious and longer lasting treatments could be useful to increase treatment intervals, thus reducing the burden of patients and caregivers and the use of healthcare resources.


Asunto(s)
Degeneración Macular , Degeneración Macular Húmeda , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Costo de Enfermedad , Estudios Transversales , Humanos , Inyecciones Intravítreas , Degeneración Macular/tratamiento farmacológico , Ranibizumab/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Estudios Retrospectivos , España/epidemiología , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológico
7.
Breast Cancer Res ; 13(2): R40, 2011 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-21466675

RESUMEN

INTRODUCTION: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. METHODS: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. RESULTS: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. CONCLUSIONS: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.


Asunto(s)
Neoplasias de la Mama/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Caenorhabditis elegans , Línea Celular , Daño del ADN , Reparación del ADN , Anemia de Fanconi/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Humanos , Ratones , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Interferencia de ARN , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Proteína de Replicación A/genética , Proteína de Replicación A/metabolismo , Factores de Riesgo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Técnicas del Sistema de Dos Híbridos
8.
PLoS One ; 16(12): e0261955, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34972174

RESUMEN

INTRODUCTION AND OBJECTIVE: Neovascular age-related macular degeneration (nAMD) leads to severe and permanent visual impairment, significantly impacting patients' quality of life and functional independence. Although treatment with anti- vascular endothelial growth factor (VEGF) prevents and, in some cases, reverses visual damage, the need for frequent monitoring visits and intravitreal injections represents a significant burden on patients, caregivers and retina specialists. OBJECTIVE: To elicit preferences for nAMD treatment characteristics from the perspectives of patients and retina specialists. METHOD: A discrete choice experiment was conducted. Participants (patients > 50 years with nAMD receiving anti-VEGF drugs for at least 2 years and without previous experience with anti-VEGF and retina specialists working in the Spanish National Healthcare System) were asked to select one of two hypothetical treatments resulting from the combination of five attributes (effects on visual function, effects on retinal fluid, treatment regimen, monitoring frequency, and cost); their levels were identified by reviewing the literature and two focus groups. The relative importance (RI) given to each attribute was estimated using a mixed logit model. The marginal rates of substitution (MRS) were calculated taking cost as the risk attribute. RESULTS: A total of 110 patients (P) [aged 79.0 (SD:7.4) years; 57.3% women; 2.3 (SD:0.7) years with nAMD; 2.1 years (SD:0.1) in treatment] and 66 retina specialists (RS) participated in the study. Participants gave greater RI to improvements in their visual function [60.0% (P); 52.7% (RS)], lower monitoring frequency [20.2% (P); 27.1% (RS)] and reduction in retinal fluid [9.8% (P); 13.0%(RS)]. Patients and retina specialists would agree to an increase in cost by 65.0% and 56.5%, respectively, in exchange for improvements of visual function; and 25.5% and 43.3% on delaying monitoring frequency by one month. CONCLUSIONS: Efficacy of treatment, in terms of visual function improvements, is the main driver for treatment election for both patients and retina specialists. Treatment monitoring requirements are also considered, mainly from the retina specialist's perspective. These results suggest that the use of more efficacious anti-VEGF agents with a longer duration of action may contribute to aligning treatment characteristics with patients/specialists' preferences. A better alignment would facilitate better disease management, fulfilling the unmet needs of patients and retina specialists.


Asunto(s)
Degeneración Macular/terapia , Médicos , Retina/fisiología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Conducta de Elección , Toma de Decisiones , Femenino , Grupos Focales , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico , Participación del Paciente , Pacientes , Riesgo , Factores Sociodemográficos , Programas Informáticos , Resultado del Tratamiento
10.
PLoS One ; 10(7): e0132546, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26167915

RESUMEN

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.


Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Neoplasias Pulmonares/sangre , Linfangioleiomiomatosis/sangre , Células Madre Neoplásicas/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/secundario , Linfangioleiomiomatosis/patología , Metástasis de la Neoplasia , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética
11.
Cell Cycle ; 9(6): 1143-55, 2010 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-20237422

RESUMEN

Studies of the role of tuberous sclerosis complex (TSC) proteins (TSC1/TSC2) in pathology have focused mainly on their capacity to regulate translation and cell growth, but their relationship with alterations of cellular structures and the cell cycle is not yet fully understood. The transforming acidic coiled-coil (TACC) domain-containing proteins are central players in structures and processes connected to the centrosome. Here, TACC3 interactome mapping identified TSC2 and 15 other physical interactors, including the evolutionary conserved interactions with ch-TOG/CKAP5 and FAM161B. TACC3 and TSC2 co-localize and co-purify with components of the nuclear envelope, and their deficiency causes morphological alterations of this structure. During cell division, TACC3 is necessary for the proper localization of phospho-Ser939 TSC2 at spindle poles and cytokinetic bridges. Accordingly, abscission alterations and increased frequency of binucleated cells were observed in Tacc3- and Tsc2-deficient cells relative to controls. In regulating cell division, TSC2 acts epistatically to TACC3 and, in addition to canonical TSC/mTOR signaling and cytokinetic associations, converges to the early mitotic checkpoint mediated by CHFR, consistently with nuclear envelope associations. Our findings link TACC3 to novel structural and cell division functions of TSC2, which may provide additional explanations for the clinical and pathological manifestations of lymphangioleiomyomatosis (LAM) disease and TSC syndrome, including the greater clinical severity of TSC2 mutations compared to TSC1 mutations.


Asunto(s)
División Celular , Proteínas Asociadas a Microtúbulos/metabolismo , Membrana Nuclear/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Núcleo Celular/metabolismo , Supervivencia Celular , Centrosoma/metabolismo , Citocinesis , Epistasis Genética , Células HEK293 , Células HeLa , Humanos , Ratones , Proteínas Asociadas a Microtúbulos/deficiencia , Mitosis , Fosfoserina/metabolismo , Unión Proteica , Transporte de Proteínas , Huso Acromático/metabolismo , Fracciones Subcelulares/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/deficiencia
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