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1.
Cell ; 157(2): 382-394, 2014 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-24725405

RESUMEN

Missense mutations in the p53 tumor suppressor inactivate its antiproliferative properties but can also promote metastasis through a gain-of-function activity. We show that sustained expression of mutant p53 is required to maintain the prometastatic phenotype of a murine model of pancreatic cancer, a highly metastatic disease that frequently displays p53 mutations. Transcriptional profiling and functional screening identified the platelet-derived growth factor receptor b (PDGFRb) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, noninvasive cells. Blocking PDGFRb signaling by RNA interference or by small molecule inhibitors prevented pancreatic cancer cell invasion in vitro and metastasis formation in vivo. Finally, high PDGFRb expression correlates with poor disease-free survival in pancreatic, colon, and ovarian cancer patients, implicating PDGFRb as a prognostic marker and possible target for attenuating metastasis in p53 mutant tumors.


Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Metástasis de la Neoplasia , Neoplasias Pancreáticas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Carcinoma Ductal Pancreático/patología , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Humanos , Ratones , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteína p53 Supresora de Tumor/genética
2.
Genes Dev ; 29(12): 1298-315, 2015 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-26080815

RESUMEN

Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.


Asunto(s)
Neoplasias de la Mama/fisiopatología , Ensamble y Desensamble de Cromatina/genética , Regulación Neoplásica de la Expresión Génica , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Línea Celular Tumoral , Proteínas Cromosómicas no Histona/metabolismo , Células HT29 , Humanos , Células MCF-7 , Mutación/genética , Nucleosomas/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , Conformación Proteica , Factores de Transcripción/metabolismo
3.
Cancer ; 125(16): 2782-2793, 2019 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-31012957

RESUMEN

BACKGROUND: The prognostic relevance of human papillomavirus (HPV) status in patients with nonoropharyngeal (OPX) squamous cell cancer (SCC) of the head and neck is controversial. In the current study, the authors evaluated the impact of high-risk HPV status on overall survival (OS) in patients with non-OPX SCC using a large database approach. METHODS: The National Cancer Data Base was queried to identify patients diagnosed from 2004 through 2014 with SCC of the OPX, hypopharynx (HPX), larynx, and oral cavity (OC) with known HPV status. Survival was estimated using Kaplan-Meier methods; distributions were compared using log-rank tests. Propensity score-matching and inverse probability of treatment weighing (IPTW) methods were used; cohorts were matched based on age, sex, Charlson-Deyo score, clinical American Joint Committee on Cancer (AJCC) group stage, treatments received, and anatomic subsite. Propensity analyses were stratified by group stage of disease. RESULTS: A total of 24,740 patients diagnosed from 2010 through 2013 were analyzed: 1085 patients with HPX, 4804 with laryngeal, 4,018 with OC, and 14,833 with OPX SCC. The percentages of HPV-positive cases by disease site were 17.7% for HPX, 11% for larynx, 10.6% for OC, and 62.9% for OPX. HPV status was found to be prognostic in multiple unadjusted and propensity-adjusted non-OPX populations. HPV positivity was associated with superior OS in patients with HPX SCC with a hazard ratio (HR) of 0.61 (P < .001 by IPTW), in patients with AJCC stage III to IVB laryngeal SCC (HR, 0.79; P = .019 by IPTW), and in patients with AJCC stage III to IVB OC SCC (HR, 0.78; P = .03 by IPTW). CONCLUSIONS: Positive high-risk HPV status appears to be associated with longer OS in multiple populations of patients with non-OPX head and neck disease (HPX, locally advanced larynx, and OC). If prospectively validated, these findings have implications for risk stratification.


Asunto(s)
Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/complicaciones , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Bases de Datos Factuales , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neoplasias Orofaríngeas/patología , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Estados Unidos/epidemiología
4.
Proc Natl Acad Sci U S A ; 113(41): E6107-E6116, 2016 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-27681615

RESUMEN

The p53-related transcription factor p63 is required for maintenance of epithelial cell differentiation. We found that activated forms of the Harvey Rat Sarcoma Virus GTPase (H-RAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) oncogenes strongly repress expression of ∆Np63α, the predominant p63 isoform in basal mammary epithelial cells. This regulation occurs at the transcriptional level, and a short region of the ∆Np63 promoter is sufficient for repression induced by H-RasV12. The suppression of ∆Np63α expression by these oncogenes concomitantly leads to an epithelial-to-mesenchymal transition (EMT). In addition, the depletion of ∆Np63α alone is sufficient to induce EMT. Both H-RasV12 expression and ∆Np63α depletion induce individual cell invasion in a 3D collagen gel in vitro system, thereby demonstrating how Ras can drive the mammary epithelial cell state toward greater invasive ability. Together, these results suggest a pathway by which RAS and PIK3CA oncogenes induce EMT through regulation of ∆Np63α.


Asunto(s)
Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/genética , Regulación de la Expresión Génica , Mutación , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Proteínas ras/genética , Secuencia de Bases , Sitios de Unión , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Genes Reporteros , Humanos , Modelos Biológicos , Fosfatidilinositol 3-Quinasas/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Eliminación de Secuencia , Transducción de Señal , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/metabolismo
5.
RNA ; 21(6): 1147-58, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25904135

RESUMEN

CRISPR-Cas immune systems function to defend prokaryotes against potentially harmful mobile genetic elements including viruses and plasmids. The multiple CRISPR-Cas systems (Types I, II, and III) each target destruction of foreign nucleic acids via structurally and functionally diverse effector complexes (crRNPs). CRISPR-Cas effector complexes are comprised of CRISPR RNAs (crRNAs) that contain sequences homologous to the invading nucleic acids and Cas proteins specific to each immune system type. We have previously characterized a crRNP in Pyrococcus furiosus (Pfu) that contains Cmr (Type III-B) Cas proteins associated with one of two size classes of crRNAs and cleaves complementary target RNAs. Here, we have isolated and characterized two additional native Pfu crRNPs containing either Csa (Type I-A) or Cst (Type I-G) Cas proteins and distinct profiles of associated crRNAs. For each complex, the Cas proteins were identified by mass spectrometry and immunoblotting and the crRNAs by RNA sequencing and Northern blot analysis. The crRNAs associated with both the Csa and Cst complexes originate from all seven Pfu CRISPR loci and contain identical 5' ends (8-nt repeat-derived 5' tag sequences) but heterogeneous 3' ends (containing variable amounts of downstream repeat sequences). These crRNA forms are distinct from Cmr-associated crRNAs, indicating different 3' end processing pathways following primary cleavage of common pre-crRNAs. Like other previously characterized Type I CRISPR-Cas effector complexes, we predict that the newly identified Pfu Csa and Cst crRNPs each function to target invading DNA, adding an additional layer of protection beyond that afforded by the previously characterized RNA targeting Cmr complex.


Asunto(s)
Sistemas CRISPR-Cas , Pyrococcus furiosus/genética , Pyrococcus furiosus/metabolismo , ARN de Archaea/genética , Ribonucleoproteínas/aislamiento & purificación , Proteínas Arqueales/aislamiento & purificación , Proteínas Arqueales/metabolismo , Proteínas Asociadas a CRISPR/aislamiento & purificación , Proteínas Asociadas a CRISPR/metabolismo , Espectrometría de Masas , Datos de Secuencia Molecular , ARN de Archaea/metabolismo , Ribonucleoproteínas/metabolismo , Análisis de Secuencia de ARN
6.
Nat Commun ; 15(1): 8854, 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39402027

RESUMEN

Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.


Asunto(s)
Neoplasias Encefálicas , Dexametasona , Radiocirugia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Linfocitos T CD8-positivos/inmunología , Terapia Combinada , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Proyectos Piloto , Estudios Prospectivos , Radiocirugia/métodos , Estudios Retrospectivos , Resultado del Tratamiento
7.
Adv Radiat Oncol ; 8(2): 101155, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36845623

RESUMEN

Purpose: Anal cancer affects a disproportionate percentage of persons infected with human immunodeficiency virus (HIV). We analyzed a cohort of patients with HIV and anal cancer who received modern radiation therapy (RT) and concurrent chemotherapy to assess whether certain factors are associated with poor oncologic outcomes. Patients and Methods: We performed a retrospective chart review of 75 consecutive patients with HIV infection and anal cancer who received definitive chemotherapy and RT from 2008 to 2018 at a single academic institution. Local recurrence, overall survival, changes in CD4 counts, and toxicities were investigated. Results: Most patients were male (92%) with large representation from Black patients (77%). The median pretreatment CD4 count was 280 cells/mm3, which was persistently lower at 6 and 12 months' posttreatment, 87 cells/mm3 and 182 cells/mm3, respectively (P < .001). Most (92%) patients received intensity modulated RT; median dose was 54 Gy (Range, 46.8-59.4 Gy). At a median follow-up 5.4 years (Range, 4.37-6.21 years), 20 (27%) patients had disease recurrence and 10 (13%) had isolated local failures. Nine patients died due to progressive disease. In multivariable analysis, clinically node negative involvement was significantly associated with better overall survival (hazard ratio, 0.39; 95% confidence interval, 0.16-1.00, P = .049). Acute grade 2 and 3 skin toxicities were common, at 83% and 19%, respectively. Acute grade 2 and 3 gastrointestinal toxicities were 9% and 3%, respectively. Acute grade 3 hematologic toxicity was 20%, and one grade 5 toxicity was reported. Several late grade 3 toxicities persisted: gastrointestinal (24%), skin (17%), and hematologic (6%). Two late grade 5 toxicities were noted. Conclusions: Most patients with HIV and anal cancer did not experience local recurrence; however, acute and late toxicities were common. CD4 counts at 6 and 12 months' posttreatment remained lower than pretreatment CD4 counts. Further attention to treatment of the HIV-infected population is needed.

8.
RNA ; 16(11): 2181-8, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20884784

RESUMEN

The CRISPR-Cas system provides many prokaryotes with acquired resistance to viruses and other mobile genetic elements. The core components of this defense system are small, host-encoded prokaryotic silencing (psi)RNAs and Cas (CRISPR-associated) proteins. Invader-derived sequences within the psiRNAs guide Cas effector proteins to recognize and silence invader nucleic acids. Critical for CRISPR-Cas defense is processing of the psiRNAs from the primary transcripts of the host CRISPR (clustered regularly interspaced short palindromic repeat) locus. Cas6, a previously identified endoribonuclease present in a wide range of prokaryotes with the CRISPR-Cas system, binds and cleaves within the repeat sequences that separate the individual invader targeting elements in the CRISPR locus transcript. In the present study, we investigated several key aspects of the mechanism of function of Cas6 in psiRNA biogenesis. RNA footprinting reveals that Pyrococcus furiosus Cas6 binds to a 7-nt (nucleotide) sequence near the 5' end of the CRISPR RNA repeat sequence, 14 nt upstream of the Cas6 cleavage site. In addition, analysis of the cleavage activity of P. furiosus Cas6 proteins with mutations at conserved residues suggests that a triad comprised of Tyr31, His46, and Lys52 plays a critical role in catalysis, consistent with a possible general acid-base RNA cleavage mechanism for Cas6. Finally, we show that P. furiosus Cas6 remains stably associated with its cleavage products, suggesting additional roles for Cas6 in psiRNA biogenesis.


Asunto(s)
Endorribonucleasas/metabolismo , Pyrococcus furiosus/enzimología , ARN/metabolismo , Secuencia de Bases , Sitios de Unión , Biocatálisis , Endorribonucleasas/genética , Silenciador del Gen , Mutación , ARN/genética , Especificidad por Sustrato
9.
Clin Breast Cancer ; 20(6): e701-e710, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32665190

RESUMEN

BACKGROUND: Two large randomized trials, CALGB 9343 and PRIME II, support omission of radiotherapy after breast conserving surgery (BCS) in elderly women with favorable-risk early stage breast cancer intending to take endocrine therapy. However, patients with grade 3 histology were underrepresented on these trials. We hypothesized that high-grade disease may be unsuitable for treatment de-escalation and report the oncologic outcomes for elderly women with favorable early stage breast cancer treated with BCS with or without radiotherapy. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was queried for women between 70 and 79 years of age with invasive ductal carcinoma diagnosed between 1998 and 2007. This cohort was narrowed to women with T1mic-T1c, N0, estrogen receptor-positive, invasive ductal carcinoma treated with BCS with or without external beam radiation (EBRT). The primary endpoints were 5- and 10-year cause-specific survival (CSS). Univariate and multivariate analyses were performed. Propensity-score matching of T-stage, year of diagnosis, and age was utilized to reduce selection bias while comparing treatment arms within the grade 3 subgroup. RESULTS: A total of 12,036 women met inclusion criteria, and the median follow-up was 9.4 years. EBRT was omitted in 22% of patients, including 21% with grade 3 disease. Patients in the EBRT cohort were slightly younger (median, 74 vs. 75 years; P < .01) and had fewer T1a tumors (11% vs. 13%; P = .02). Histologic grades 1, 2, and 3 comprised 36%, 50%, and 14% of the cohort, respectively, and there were no differences in EBRT utilization by grade. Utilization of EBRT decreased following the publication of the CALGB trial in 2004 decreasing from 82% to 85% in 1998 to 2000 to 73% to 75% in 2005 to 2007 (P < .01). Unadjusted outcomes showed that in grade 1 disease, there were no differences in CSS with or without EBRT at 5 (99%) and 10 years (95%-96%). EBRT was associated with an improvement in CSS in grade 2 histology at 5 years (97% vs. 98%) and 10 years (92% vs. 95%) (P = .004). The benefit was more pronounced in grade 3 disease with CSS increasing from 93% to 96% at 5 years and from 87% to 92% at 10 years (P = .02) with EBRT. In the grade 3 subgroup, propensity-score matching confirmed EBRT was associated with superior CSS compared with surgery alone (hazard ratio, 0.58; 95% confidence interval, 0.34-0.98; P = .043). CONCLUSION: In this database analysis, omission of radiotherapy after BCS in elderly women with favorable-risk, early stage, grade 3 breast cancer was associated with inferior CSS. Further prospective data in this patient population are needed to confirm our findings and conclusions.


Asunto(s)
Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/terapia , Mastectomía Segmentaria/estadística & datos numéricos , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Clasificación del Tumor , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante/estadística & datos numéricos , Programa de VERF/estadística & datos numéricos , Resultado del Tratamiento
10.
Pract Radiat Oncol ; 10(1): 36-43, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31586666

RESUMEN

PURPOSE: Stereotactic radiosurgery (SRS) is increasingly used in the management of patients with resected brain metastases (rBMs). A significant complication of this therapy can be radiation necrosis (RN). Despite radiation therapy dose de-escalation and the delivery of several rather than a single dose fraction, rates of RN after SRS for rBMs remain high. We evaluated the dosimetric parameters associated with radiographic RN for rBMs. METHODS AND MATERIALS: From 2008 to 2016, 55 rBMs at a single institution that were treated postoperatively with 5-fraction linear accelerator-based SRS (25-35 Gy) with minimum 3 months follow-up were evaluated. For each lesion, variables recorded included radiation therapy dose to normal brain, location and magnitude of hotspots, clinical target volume (CTV), and margin size. Hotspot location was stratified as within the tumor bed alone (CTV) or within the planning target volume (PTV) expansion margin volume (PTV minus CTV). Cumulative incidence with competing risks was used to estimate rates of RN and local recurrence. Optimal cut-points predicting for RN for hotspot magnitude based on location were identified via maximization of the log-rank test statistic. RESULTS: Median age for all patients was 58.5 years. For all targets, the median CTV was 17.53 cm3, the median expansion margin to PTV was 2 mm, and the median max hotspot was 111%. At 1 year, cumulative incidence of radiographic RN was 18.2%. Univariate analysis showed that max hotspots with a hazard ratio of 3.28 (P = .045), hotspots within the PTV expansion margin with relative magnitudes of 105%, 110%, and 111%, and an absolute dose of 33.5 Gy predicted for RN (P = .029, P = .04, P = .038, and P = .0488, respectively), but hotspots within the CTV did not. CONCLUSIONS: To our knowledge, this is the first study that investigated dosimetric factors that predict for RN after 5-fraction hypofractionated SRS for rBM. Hotspot location and magnitude appear important for predicting RN risk, thus these parameters should be carefully considered during treatment planning.


Asunto(s)
Neoplasias Encefálicas/terapia , Encéfalo/patología , Traumatismos por Radiación/epidemiología , Radiocirugia/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de la radiación , Encéfalo/cirugía , Neoplasias Encefálicas/secundario , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Necrosis/diagnóstico por imagen , Necrosis/epidemiología , Necrosis/etiología , Aceleradores de Partículas , Hipofraccionamiento de la Dosis de Radiación , Traumatismos por Radiación/diagnóstico por imagen , Traumatismos por Radiación/etiología , Traumatismos por Radiación/patología , Radiometría/estadística & datos numéricos , Radiocirugia/instrumentación , Radiocirugia/métodos , Factores de Riesgo , Adulto Joven
11.
Oncogene ; 39(25): 4798-4813, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32457468

RESUMEN

Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor outcomes associated with resistance to cisplatin-based chemotherapy. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2), which silences transcription through trimethylation of histone H3 lysine 27 (H3K27me3) and has emerged as an important therapeutic target with inhibitors targeting its methyltransferase activity under clinical investigation. Here, we show that EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair (NER) and govern cisplatin resistance in SCLC. Using a synthetic lethality screen, we identified important regulators of cisplatin resistance in SCLC cells, including EZH2. EZH2 depletion causes cellular cisplatin and UV hypersensitivity in an epistatic manner with DDB1-DDB2. EZH2 complexes with DDB1-DDB2 and promotes DDB2 stability by impairing its ubiquitination independent of methyltransferase activity or PRC2, thereby facilitating DDB2 localization to cyclobutane pyrimidine dimer crosslinks to govern their repair. Furthermore, targeting EZH2 for depletion with DZNep strongly sensitizes SCLC cells and tumors to cisplatin. Our findings reveal a non-catalytic and PRC2-independent function for EZH2 in promoting NER through DDB2 stabilization, suggesting a rationale for targeting EZH2 beyond its catalytic activity for overcoming cisplatin resistance in SCLC.


Asunto(s)
Reparación del ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Cisplatino/uso terapéutico , ADN/genética , ADN/metabolismo , Reparación del ADN/efectos de los fármacos , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Complejo Represivo Polycomb 2/genética , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo
12.
Artículo en Inglés | MEDLINE | ID: mdl-27836911

RESUMEN

TP53 missense mutations produce a mutant p53 protein that cannot activate the p53 tumor suppressive transcriptional response, which is the primary selective pressure for TP53 mutation. Specific codons of TP53, termed hotspot mutants, are mutated at elevated frequency. Hotspot forms of mutant p53 possess oncogenic properties in addition to being deficient in tumor suppression. Such p53 mutants accumulate to high levels in the cells they inhabit, causing transcriptional alterations that produce pro-oncogenic activities, such as increased pro-growth signaling, invasiveness, and metastases. These forms of mutant p53 very likely use features of wild-type p53, such as interactions with the transcriptional machinery, to produce oncogenic effects. In this review, we discuss commonalities between wild-type and mutant p53 proteins with an emphasis on transcriptional processes.


Asunto(s)
Mutación Missense , Neoplasias/genética , Proteína p53 Supresora de Tumor/fisiología , Regulación Neoplásica de la Expresión Génica , Humanos , Mutación , Transducción de Señal , Transcripción Genética , Activación Transcripcional , Proteína p53 Supresora de Tumor/genética
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