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1.
Elife ; 5: e07101, 2016 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-26956429

RESUMEN

Genetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mammary epithelial cells. We identified transglutaminase 2 (TGM2) as a putative tumor suppressor in the TP53 pathway. TGM2 suppressed colony formation in soft agar and tumor formation in a xenograft mouse model. The depletion of growth supplements induced both TGM2 expression and autophagy in a TP53-dependent manner, and TGM2 promoted autophagic flux by enhancing autophagic protein degradation and autolysosome clearance. Reduced expression of both CDKN1A, which regulates the cell cycle downstream of TP53, and TGM2 synergized to promote oncogenic transformation. Our findings suggest that TGM2-mediated autophagy and CDKN1A-mediated cell cycle arrest are two important barriers in the TP53 pathway that prevent oncogenic transformation.


Asunto(s)
Autofagia , Transformación Celular Neoplásica , Células Epiteliales/enzimología , Células Epiteliales/fisiología , Proteínas de Unión al GTP/metabolismo , Transglutaminasas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proteínas de Unión al GTP/genética , Pruebas Genéticas , Xenoinjertos , Humanos , Neoplasias Mamarias Experimentales/patología , Ratones , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas/genética
2.
PLoS One ; 10(7): e0134408, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26221963

RESUMEN

PURPOSE: The National Comprehensive Cancer Network (NCCN) has proposed guidelines for the genetic testing of the BRCA1 and BRCA2 genes, based on studies in western populations. This current study assessed potential predictive factors for BRCA mutation probability, in an Asian population. METHODS: A total of 359 breast cancer patients, who presented with either a family history (FH) of breast and/or ovarian cancer or early onset breast cancer, were accrued at the National Cancer Center Singapore (NCCS). The relationships between clinico-pathological features and mutational status were calculated using the Chi-squared test and binary logistic regression analysis. RESULTS: Of 359 patients, 45 (12.5%) had deleterious or damaging missense mutations in BRCA1 and/or BRCA2. BRCA1 mutations were more likely to be found in ER-negative than ER-positive breast cancer patients (P=0.01). Moreover, ER-negative patients with BRCA mutations were diagnosed at an earlier age (40 vs. 48 years, P=0.008). Similarly, triple-negative breast cancer (TNBC) patients were more likely to have BRCA1 mutations (P=0.001) and that these patients were diagnosed at a relatively younger age than non-TNBC patients (38 vs. 46 years, P=0.028). Our analysis has confirmed that ER-negative status, TNBC status and a FH of hereditary breast and ovarian cancer (HBOC) are strong factors predicting the likelihood of having BRCA mutations. CONCLUSIONS: Our study provides evidence that TNBC or ER-negative patients may benefit from BRCA genetic testing, particularly younger patients (<40 years) or those with a strong FH of HBOC, in Asian patients.


Asunto(s)
Pueblo Asiatico/genética , Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Pruebas Genéticas/métodos , Adulto , Factores de Edad , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Distribución de Chi-Cuadrado , Análisis Mutacional de ADN/métodos , Análisis Mutacional de ADN/estadística & datos numéricos , Femenino , Pruebas Genéticas/estadística & datos numéricos , Humanos , Modelos Logísticos , Persona de Mediana Edad , Mutación Missense , Valor Predictivo de las Pruebas , Receptores de Estrógenos/metabolismo , Factores de Riesgo , Singapur , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Adulto Joven
3.
Sci Rep ; 5: 9737, 2015 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-26024509

RESUMEN

Oxidative stress (OS) is caused by an imbalance between pro- and anti-oxidant reactions leading to accumulation of reactive oxygen species within cells. We here investigate the effect of OS on the transcriptome of human fibroblasts. OS causes a rapid and transient global induction of transcription characterized by pausing of RNA polymerase II (PolII) in both directions, at specific promoters, within 30 minutes of the OS response. In contrast to protein-coding genes, which are commonly down-regulated, this novel divergent, PolII pausing-phenomenon leads to the generation of thousands of long noncoding RNAs (lncRNAs) with promoter-associated antisense lncRNAs transcripts (si-paancRNAs) representing the major group of stress-induced transcripts. OS causes transient dynamics of si-lncRNAs in nucleus and cytosol, leading to their accumulation at polysomes, in contrast to mRNAs, which get depleted from polysomes. We propose that si-lncRNAs represent a novel component of the transcriptional stress that is known to determine the outcome of immediate-early and later cellular stress responses and we provide insights on the fate of those novel mature lncRNA transcripts by showing that their association with polysomal complexes is significantly increased in OS.


Asunto(s)
Genoma Humano , Estrés Oxidativo , ARN Mensajero/genética , ARN no Traducido/genética , Transcriptoma , Sitios de Unión , Línea Celular , Inmunoprecipitación de Cromatina , Biología Computacional/métodos , Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Regiones Promotoras Genéticas , Biosíntesis de Proteínas , ARN Polimerasa II/metabolismo , ARN Polimerasa III/metabolismo , ARN sin Sentido/genética , ARN Largo no Codificante/clasificación , ARN Largo no Codificante/genética , Factores de Transcripción/metabolismo
4.
Cancer Res ; 69(11): 4818-26, 2009 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-19487292

RESUMEN

Mutations in the p53 tumor suppressor are the most common genetic events in human cancer. These mutations not only result in a loss of wild-type p53 activity, but can also lead to a gain of new oncogenic properties. Understanding how these gained functions are regulated is in its infancy. In this study, we show that the promyelocytic leukemia (PML) protein is an important regulator of mutant p53. We show that PML interacts with mutant p53. Importantly, PML enhances the transcriptional activity of mutant p53. Unexpectedly, PML is required for the proliferation and colony formation of cancer cells bearing mutant p53. Down-regulation of PML expression inhibits the growth of mutant p53-expressing cancer cells, predominantly by promoting cell cycle arrest. Our results suggest that the tumor suppression function of PML depends on the status of p53. In the context of mutant p53, PML enhances its cancer-promoting activities.


Asunto(s)
Proteínas Nucleares/fisiología , Factores de Transcripción/fisiología , Proteína p53 Supresora de Tumor/fisiología , Proteínas Supresoras de Tumor/fisiología , Proliferación Celular , Transformación Celular Neoplásica/genética , Daño del ADN/genética , Técnicas de Silenciamiento del Gen , Genes Dominantes/genética , Células HCT116 , Células HT29 , Humanos , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Mutantes/fisiología , Neoplasias/genética , Neoplasias/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteína de la Leucemia Promielocítica , Unión Proteica , Estructura Terciaria de Proteína/fisiología , Transporte de Proteínas , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional/genética , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
5.
Liver Int ; 24(3): 218-26, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15189273

RESUMEN

BACKGROUND: A major drawback of allogeneic hepatocyte transplantation is the lack of sustained survival of the transplanted cells in the recipient liver parenchyma. The purpose of this study was to determine the effect of the presence or absence of hepatic extracellular matrix (ECM) molecules on hepatocyte survival and function following hepatocyte isolation for transplantation purposes, and the role of beta1-integrin molecules therein. METHODS: Hepatocytes, either untreated or treated with anti-beta1 integrin antibodies or RGD peptides, were seeded on wells precoated with collagen type I, type IV, laminin, fibronectin or polyhydroxyethylmehacrylate. The extent of attachment and apoptosis was evaluated. RESULTS: When hepatocytes were added into wells precoated with either fibronectin, or collagen type IV, rapid spreading and prolonged survival occurred, in contrast to hepatocytes that were seeded in wells precoated with collagen type I or polyhydroxyethylmehacrylate. Pretreatment of the cells with anti-beta1-integrin antibodies resulted in reduction of cell attachment to laminin, fibronectin, collagen I, and collagen IV. Synthetic RGD (arginine-glycine-aspartate)-peptides and anti-beta1 antibodies inhibited apoptosis of cultured hepatocytes. CONCLUSIONS: Our findings indicate that embedding of hepatocytes within their normal liver ECM surroundings maintains their survival. When detached from their natural surrounding hepatocytes enter into apoptosis, unless treated with anti-beta1-integrin antibodies or RGD peptides. This knowledge will allow improvement of hepatocyte transplantation efficiency.


Asunto(s)
Matriz Extracelular/fisiología , Hepatocitos/fisiología , Integrina beta1/fisiología , Hígado/metabolismo , Animales , Anoicis , Anticuerpos Monoclonales/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3 , Caspasas/metabolismo , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colágeno Tipo IV/farmacología , Fragmentación del ADN , Electroforesis , Femenino , Fibronectinas/farmacología , Inmunohistoquímica , Integrina beta1/inmunología , Oligopéptidos/farmacología , Ratas , Ratas Endogámicas BN
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