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1.
Shock ; 57(2): 309-315, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34907119

RESUMEN

ABSTRACT: ERG (ETS-related gene) is a member of the ETS (Erythroblast-transformation specific) family of transcription factors abundantly present in vascular endothelial cells. Recent studies demonstrate that ERG has important roles in blood vessel stability and angiogenesis. However, it is unclear how ERG is potentially involved in microvascular barrier functions and permeability. A wide variety of diseases and clinical conditions including trauma-hemorrhagic shock and burn injury are associated with microvascular dysfunctions, which causes excessive microvascular permeability, tissue edema and eventually, multiple organ dysfunction and death. The main purpose of this study was to determine the specific role of ERG in regulating microvascular permeability in human lung microvascular endothelial cells (HLMEC) and to evaluate if exogenous ERG will protect the barrier. The HLMECs were grown on Transwell inserts as monolayers and were transfected with ERG CRISPR/cas9 knockdown plasmid, ERG CRISPR activation plasmid, recombinant ERG protein or their respective controls. Recombinant vascular endothelial growth factor (VEGF) was used as an inducer of permeability for evaluating the effect of ERG activation on permeability. Changes in barrier integrity and permeability were studied using monolayer permeability assay and immunofluorescence of adherens junction proteins (VE-cadherin and ß-catenin) respectively. CRISPR/cas9-based ERG knockdown as well as VEGF treatment induced monolayer hyperpermeability, VE-cadherin, and ß-catenin junctional relocation and cytoskeletal F-actin stress fiber formation. CRISPR based ERG activation and recombinant ERG transfection attenuated VEGF-induced monolayer hyperpermeability. ERG activation preserved the adherens junctions and cytoskeleton. These results demonstrate that ERG is a potent regulator of barrier integrity and permeability in human lung microvascular endothelial cells and endogenously or exogenously enhancing ERG provides protection against barrier dysfunction and hyperpermeability.


Asunto(s)
Uniones Adherentes/genética , Permeabilidad Capilar/genética , Células Endoteliales , Endotelio Vascular/citología , Microvasos , Activación Transcripcional , Células Cultivadas , Humanos , Regulador Transcripcional ERG/genética
2.
Artículo en Inglés | MEDLINE | ID: mdl-33860286

RESUMEN

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that has a high mortality rate and disproportionately affects young African American (AA) women who carry mutations in the BRCA1 gene. Approximately 80% of breast cancers which develop in BRCA1-mutant carriers will have TNBC and the molecular mechanism facilitating tumor development is unclear. Our earlier work suggested Ubc9 to play a critical role in BRCA1 loss mediated TNBC cell migration and metastasis. Collagen is one of the major components of the stromal extracellular matrix (ECM) network that influences tissue density. Its re-organization act as a scaffold aiding cancer cells to migrate causing metastasis. Ubc9 is known to increase the production of collagen, a key component of fibroglandular breast tissue, as well as tumorigenesis. Our work is based on the hypothesis that loss of BRCA1 in women with high breast density causes abnormal Ubc9 levels which upregulates collagen, fibronectin and inhibits SIRT1, ß-catenin expression facilitating TNBC. We tested this hypothesis by studying the expression of total collagen, fibronectin, Ubc9, SIRT1, ß-catenin in BRCA1 mutant TNBC cells and tumor sample derived from patient with dense breasts using immunofluorescence, immunohistochemistry, and collagen assay. Our results suggest for the first time that mutation or loss of BRCA1 function in women with fibrocystic breasts can lead to over expression of Ubc9, induction of collagen and; fibronectin, inhibition of SIRT1 and nuclear accumulation of ß-catenin which could contribute to TNBC development. This network will aid not only in the identification of potential mechanism-based biomarkers that could detect disease early, but also enforce preventive measures that could reduce the risk for TNBC in women with high MD thus reducing the mortality associated with these cancers to achieve health equity.

3.
Integr Mol Med ; 4(4)2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31341634

RESUMEN

Triple negative breast cancer (TNBC) is a heterogeneous disease and has a higher rate of recurrence and distant metastasis. African-American (AA) women have a higher frequency of BRCA1 mutations and TNBC compared to other populations. Basal-like tumors have a higher rate of brain, lung and distant nodal metastasis more than other TNBC subtypes, contributing to higher mortality rate. Our previous work suggested Ubc9, a SUMO E2-conjugating enzyme to induce proliferation and migration of BRCA1-incompetent TNBC cells and TNBC cell lines established from the pleural effusion metastasis of a woman with TNBC. To understand the downstream signaling axis involved in distant metastasis we have used clinically relevant BRCA1 mutant and lung metastatic TNBC cell lines and our results show deregulated expression of caveolin-1, VEGF and SIRT1 in these cells compared to normal mammary epithelial cells by immunofluorescence analysis. We observed SIRT1 to be induced by wild type BRCA1a and BRCA1a I26A mutant unlike the disease associated Ubc9 binding mutants in TNBC cells. Knock down of Ubc9 induced SIRT1 expression in TNBC and ER-α expression in breast cancer cells. This is the first report demonstrating a role for Ubc9 in repressing both SIRT1 and ER-α expression in BRCA1 associated TNBC cells. It also suggests that the BARD-dependent E3 Ubiquitin ligase and HR (homologous recombination) activity of BRCA1 may not be required for inducing SIRT1 expression. Our results suggest for the first time that in BRCA1 mutant TNBC Ubc9-mediated induction of VEGF, inhibition of caveolin-1, SIRT1 and ER-α expression as a novel molecular mechanism underlying TNBC EMT (epithelial mesenchymal transition) leading to lung metastasis with pleural effusion. Drugs that target Ubc9 to both induce SIRT1 and ER-α or using SIRT1 agonists in combination with chemotherapy can be used as a promising targeted therapeutic approach for treating basal-like metastatic BRCA1-linked TNBC thus reducing the mortality in patients with TNBC.

4.
J Nutr Metab ; 2016: 4280876, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27313879

RESUMEN

Class II invariant chain peptide (CLIP) expression has been demonstrated to play a pivotal role in the regulation of B cell function after nonspecific polyclonal expansion. Several studies have shown vitamin D3 helps regulate the immune response. We hypothesized that activated vitamin D3 suppresses CLIP expression on activated B-cells after nonspecific activation or priming of C57BL/6 mice with CpG. This study showed activated vitamin D3 actively reduced CLIP expression and decreased the number of CLIP(+) B-lymphocytes in a dose and formulation dependent fashion. Flow cytometry was used to analyze changes in mean fluorescent intensity (MFI) based on changes in concentration of CLIP on activated B-lymphocytes after treatment with the various formulations of vitamin D3. The human formulation of activated vitamin D (calcitriol) had the most dramatic reduction in CLIP density at an MFI of 257.3 [baseline of 701.1 (P value = 0.01)]. Cholecalciferol and alfacalcidiol had no significant reduction in MFI at 667.7 and 743.0, respectively. Calcitriol seemed to best reduce CLIP overexpression in this ex vivo model. Bioactive vitamin D3 may be an effective compliment to other B cell suppression therapeutics to augment downregulation of nonspecific inflammation associated with many autoimmune disorders. Further study is necessary to confirm these findings.

5.
J Cancer Epidemiol Treat ; 1(1): 6-10, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-27774311

RESUMEN

BACKGROUND: The incidence of anal carcinoma has increased over the last few decades especially in African Americans (AA) despite the use of highly active anti-retroviral therapy (HAART). Here, we retrospectively review oncologic outcomes of AA patients with anal squamous cell carcinoma (SCC) with and without HIV to further examine the cause of this trend. MATERIALS AND METHODS: All adult AA patients diagnosed with anal SCC from 2000 to 2007 who met inclusion were examined. All patients were staged according to the American Joint Committee on Carcinoma (AJCC) sixth edition staging classification. Patients were divided into two cohorts: HIV (-) and HIV (+). Demographics, comorbidities, and oncologic outcomes were analyzed. RESULTS: Twenty-two AA patients with anal SCC were analyzed. Fifteen (68.%) were HIV (+) and seven (32%) were negative. Seventy-four percent of HIV (+) patients were on HAART therapy at the time of diagnosis. The HIV (+) cohort was significantly younger, mostly male, and had more comorbidities compared to the negative cohort. There was no difference in tumor, nodal or metastasis (TNM) stage for both cohorts. HIV (+) patients were more likely to receive non-operative therapy. The 5-year survival rate for HIV negative and positive patients was 57% and 58%, respectively. AJCC stage was the only factor predictive of survival after performing Cox hazard proportional regression analysis, HR: 1.96 (95% CI, 0.987 to 3.881). CONCLUSIONS: In the HAART era, HIV (+) AA patients are at high risk of developing anal SCC. However, the prognosis of HIV (+) AA with anal SSC is similar to that of their HIV (-) counterparts. Carcinoma stage is the only factor predictive of survival.

6.
J Pharm Sci Pharmacol ; 2(3): 208-216, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28497076

RESUMEN

In the United States of America, prostate cancer is the second most common age-related cancer among men. African-American men have the highest incidence of, and mortality rate from this disease in the United States. According to the American Cancer Society, 29% of all cancer cases and 9% of all cancer deaths are a result of prostate cancer. Individuals who are at highest risk include African-American men, men over 60 years of age, and those with a family history of the disease. African-Americans also have twice the risk of developing prostate cancer as compared to Caucasians. Erythroblastosis virus E26 transformation-specific (ETS) factors play an important role in human cancers. ETS Variant 1 (ETV1), an ETS factor, is notable for its association in prostate cancers, where truncated ETV1 (dETV1) or its full length counterpart is overexpressed in approximately 10% of the prostate cancer patients. Prostate cancer tumorigenesis may be initiated by deregulation of the Wnt/ß-catenin pathway. Mutations that stabilize ß-catenin were shown to contribute to the loss of cell-growth control in tumorigenesis. We hypothesized that ETV1's interaction with components of the Wnt/ß-catenin pathway may alter ß-catenin's interaction with downstream tumor-suppressor genes, which are critical in regulating apoptosis and cell-growth properties of prostate cells. Our results demonstrate for the first time that ETV1 alters ß-catenin activity by activating kinases that regulate Wnt/ß-catenin activity through post-translational modification in prostate cancer cells. We further demonstrate that therapeutic agents such as PD98059, that reverse effect of ETV1 on Wnt/ß-catenin signaling pathway, can be used to target ETV1-positive prostate cancer cells. These therapeutic agents could have a profound impact on prevention and treatment of prostate cancer which may help to reduce health disparity seen in minority patients. Understanding the role of ETV1 in Wnt/ß-catenin pathway will also allow us to develop better diagnostic tools, which can be used as a biomarker for ETV1-positive prostate cancers.

7.
World J Transl Med ; 3(1): 1-8, 2014 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-25525571

RESUMEN

Ovarian cancer is the second most common gynecological cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.

8.
J Pharm Sci Pharmacol ; 1(3): 175-181, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25745638

RESUMEN

TGF-ß/Smads signaling plays a significant role in the regulation of growth of normal and prostate cancer cells. Smad proteins function as important mediators of intracellular signal transduction of transforming growth factor-ß (TGF-ß). TGF-ß signaling pathway is known to regulate cell proliferation, differentiation, apoptosis and play a major role in some human diseases and cancers. Following their phosphorylation by TGF-ß receptor-I, Receptor-regulated Smads (including Smad2 and Smad3 proteins) form a heteromeric complex with co-Smad (Smad4) and then translocate into the nucleus where they bind and regulate the expression of target genes. ERG (Ets Related Gene) belongs to the ETS family of transcriptional factors. Chromosomal rearrangement of TMPRSS2 gene and ERG gene has been found in majority of prostate cancers. Over-expression of full length or truncated ERG proteins have been shown to associate with a higher rate of recurrent and unfavorable prognosis of prostate cancer. In order to understand how ERG oncoprotein regulates TGF-ß/Smads signaling pathway, we have studied the effect of ERG on TGF-ß/Smad3 signaling pathway. In this study, we demonstrate that ERG oncoprotein physically interacts with Smad3 protein and stabilizes phospho-Smad3 protein and thereby enhance TGF-ß/Smad3 signaling pathway in prostate cells. Thus, ERG oncoprotein plays an important role in prostate tumorigenesis by using a novel mechanism to activate TGF-ß/Smad3 signaling pathway.

9.
Artículo en Inglés | MEDLINE | ID: mdl-25594072

RESUMEN

Ovarian cancer is the second most common gynecological cancer and the five-year survival rate is only about 40%. High-grade serous carcinoma is the pre-dominant histotype associated with hereditary ovarian cancer and women with inherited mutations in BRCA1 have a lifetime risk of 40-60%. BRCA1 and its isoform BRCA1a are multifunctional proteins that are the most evolutionary conserved of all the other splice variants. Our group has previously reported that BRCA1/1a proteins, unlike K109R and C61G mutants, suppress growth of ovarian cancer cells by tethering Ubc9. In this study we found wild type BRCA1/1a proteins to induce expression of caveolin-1, a tumor suppressor in BRCA1-mutant serous epithelial ovarian cancer (SEOC) cells by immunofluorescence analysis. The K109R and C61G disease associated mutant BRCA1 proteins that do not bind Ubc9 were not as efficient in up-regulation of caveolin-1 expression in SEOC cells. Additionally, immunofluorescence analysis showed BRCA1/1a proteins to induce redistribution of Caveolin-1 from cytoplasm and nucleus to the cell membrane. This is the first study demonstrating the physiological link between loss of Ubc9 binding, loss of growth suppression and loss of Caveolin-1 induction of disease-associated mutant BRCA1 proteins in SEOC cells. Decreased Caveolin-1 expression combined with elevated Ubc9 expression can in the future be used as an early biomarker for BRCA1 mutant SEOC.

10.
J Pharm Sci Pharmacol ; 1(2): 87-100, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-25664332

RESUMEN

Ewing Sarcoma (ES) is a rare form of bone cancer that most commonly affects children and adolescents. Chromosomal translocations are fundamental to the development of Ewing Sarcoma, linked to the changes in gene expression affecting transcription factors. Histone acetyl transferases (HATs) and histone deacetylases (HDACs) regulate transcription by modifying acetylation of both histones and transcription factors. Despite the use of multimodal therapeutic approaches current therapies are associated with significant short and long-term side effects. Hence, new therapeutic approaches are needed. In this study, we show that ERG/EWS-ERG, inhibits transcriptional activation properties of RXRα. These results suggest that ERG/EWS-ERG/EWS-Fli-1 may target transcriptional co-activators and transcriptional repressors and thereby regulate RXRα transcriptional activity. To understand the molecular mechanism of action, how the fusion protein targets nuclear receptor function, and to provide a clue for the cancer health disparity seen in Ewing Sarcoma, we hypothesized that the aberrant fusion protein, EWS-ERG/EWS-Fli-1 regulates HDACs-mediated repressor complex and inhibits the binding of transcriptional activator complex causing transcriptional repression of RXRα activity. Since it is known that HDACs regulate nuclear receptors, we proposed that HDAC inhibitor, valproic acid (VPA), an anti-epileptic drug, may reverse the inhibitory properties of EWS-ERG/EWS-Fli-1 oncoprotein on RXRα transcriptional activity and might therefore be used as therapeutic agent in ES. We demonstrate that VPA reverses the inhibitory effect of EWSERG/EWS-Fli-1 on RXRα transcriptional activity and also inhibits the cell growth. Furthermore, VPA induces apoptosis and restored the expression of RXRα target genes RARß, CRABPII and p21 activity and repressed the expression of aberrant fusion proteins, EWS-ERG and EWS-Fli-1 in Ewing Sarcoma cells. Thus, therapeutic regulation of transcriptional repressor properties of EWS-ERG/EWS-Fli-1 with an anti-epileptic drug with a promising new potential might have a profound impact on prevention, management and treatment of Ewing Sarcoma. Therapeutic use of VPA in minority patients may help reduce the health disparity.

11.
J Pharm Sci Pharmacol ; 1(1): 82-85, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25679011

RESUMEN

Transforming growth factor beta (TGF-ß) signaling pathway is involved in diverse cellular processes, including cell proliferation, differentiation, adhesion, apoptosis, and some human diseases including cancer. Smad proteins function as mediators of intracellular signal transduction of TGF-ß. Following their phosphorylation by TGF-ß receptor I, Smad2 and Smad3 form a heteromeric complex with Smad4 and then are translocated into the nucleus where they bind to other co-factors and regulate the expression of target genes. ERG (Ets Related Gene) belongs to the ETS family of transcriptional factors. Chromosomal rearrangement of TMPRSS2 gene and ERG gene has been found in the majority of prostate cancers. Over-expression of full length or truncated ERG proteins is associated with a higher rate of recurrence and unfavorable prognosis. In this review, we focus on recent understanding of regulation of TGF-ß/Smads signaling pathway by ERG proteins in prostate cancer.

12.
Hereditary Genet ; 2013(Suppl 2)2013.
Artículo en Inglés | MEDLINE | ID: mdl-25285241

RESUMEN

Triple Negative Breast Cancer (TNBC) is a heterogeneous disease that based on immunohistochemistry (IHC) is estrogen receptor (ER) negative, progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) negative. TNBC is typically observed in young AA women and Hispanic women who carry a mutation in the BRCA1 gene. TNBC is characterized by a distinct molecular profile, aggressive nature and lack of targeted therapies. The purpose of this article is to review the current and future novel signalling pathways as therapeutic approaches to TNBC. Recent Identification of a new BRCA1 trafficking pathway holds promise in the future for the development of targeted therapies for TNBC.

13.
Am J Cancer Res ; 2(5): 540-8, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22957306

RESUMEN

Mutation in the BRCA1 gene is associated with increased risk for hereditary breast and ovarian cancers. In sporadic ovarian tumors, BRCA1 dysfunction is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein. Our group has previously reported that BRCA1 proteins, unlike K109R and cancer-predisposing mutant C61G BRCA1 proteins, bind the sole SUMO E2-conjugating enzyme Ubc9. In this study, we examined the result of altered Ubc9 binding and knockdown on the sub-cellular localization and growth inhibitory function of BRCA1 proteins in ovarian cancer cells. Using live imaging of YFP, RFP-tagged BRCA1 and BRCA1a proteins, our results show enhanced cytoplasmic localization of K109R and C61G mutant BRCA1 proteins in ES-2, NIHOVCAR3 and UWB 1.289 ovarian cancer cells. Down-regulation of Ubc9 in ovarian cancer cells using Ubc9 siRNA resulted in cytoplasmic localization of BRCA1 and BRCA1a proteins. These mutant BRCA1a proteins were impaired in their capacity to inhibit growth of ES-2 ovarian cancer cells. Several ovarian cancer cells, including a BRCA1-null ovarian cancer cell line, showed higher levels of expression of Ubc9. This is the first study demonstrating the physiological link between loss of Ubc9 binding and loss of growth suppression of disease-associated mutant BRCA1a proteins in ovarian cancer cells. BRCA1, by turning off or on Ubc9 binding, regulates growth of ovarian cancers.

14.
Int J Oncol ; 39(1): 111-9, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21519790

RESUMEN

An ETS family member, ETS Related Gene (ERG) is involved in the Ewing family of tumors as well as leukemias. Rearrangement of the ERG gene with the TMPRSS2 gene has been identified in the majority of prostate cancer patients. Additionally, overexpression of ERG is associated with unfavorable prognosis in prostate cancer patients similar to leukemia patients. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate transcription as well as epigenetic status of genes through acetylation of both histones and transcription factors. Deregulation of HATs and HDACs is frequently seen in various cancers, including prostate cancer. Many cellular oncogenes as well as tumor viral proteins are known to target either or both HATs and HDACs. Several studies have demonstrated that there are alterations of HDAC activity in prostate cancer cells. Recently, we found that ERG binds and inhibits HATs, which suggests that ERG is involved in deregulation of protein acetylation. Additionally, it has been shown that ERG is associated with a higher expression of HDACs. In this study, we tested the effect of the HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) on ERG-positive prostate cancer cells (VCaP). We found that VPA and TSA induce apoptosis, upregulate p21/Waf1/CIP1, repress TMPRSS2-ERG expression and affect acetylation status of p53 in VCaP cells. These results suggest that HDAC inhibitors might restore HAT activity through two different ways: by inhibiting HDAC activity and by repressing HAT targeting oncoproteins such as ERG.


Asunto(s)
Apoptosis/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Neoplasias de la Próstata/fisiopatología , Proteínas Proto-Oncogénicas c-ets/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Ácido Valproico/farmacología , Acetilación/efectos de los fármacos , Animales , Células COS , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasas/metabolismo , Humanos , Masculino , Modelos Biológicos , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-ets/genética , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismo
15.
J Cell Physiol ; 226(12): 3355-67, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21344391

RESUMEN

BRCA1 gene mutations are responsible for hereditary breast and ovarian cancers. In sporadic breast tumors, BRCA1 dysfunction or aberrant subcellular localization is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein and the reason for cytoplasmic localization of BRCA1 in young breast cancer patients is not yet known. We have previously reported BRCA1 proteins unlike K109R and cancer-predisposing mutant C61G to bind Ubc9 and modulate ER-α turnover. In the present study, we have examined the consequences of altered Ubc9 binding and knockdown on the subcellular localization and growth inhibitory function of BRCA1 proteins. Our results using live imaging of YFP, GFP, RFP-tagged BRCA1, BRCA1a and BRCA1b proteins show enhanced cytoplasmic localization of K109 R and C61G mutant BRCA1 proteins in normal and cancer cells. Furthermore, down-regulation of Ubc9 in MCF-7 cells using Ubc9 siRNA resulted in enhanced cytoplasmic localization of BRCA1 protein and exclusive cytoplasmic retention of BRCA1a and BRCA1b proteins. These mutant BRCA1 proteins were transforming and impaired in their capacity to inhibit growth of MCF-7 and CAL51 breast cancer cells. Interestingly, cytoplasmic BRCA1a mutants showed more clonogenicity in soft agar and higher levels of expression of Ubc9 than parental MCF7 cells. This is the first report demonstrating the physiological link between cytoplasmic mislocalization of mutant BRCA1 proteins, loss of ER-α repression, loss of ubiquitin ligase activity and loss of growth suppression of BRCA1 proteins. Thus, binding of BRCA1 proteins to nuclear chaperone Ubc9 provides a novel mechanism for nuclear import and control of tumor growth.


Asunto(s)
Proteína BRCA1/metabolismo , Neoplasias de la Mama/metabolismo , Núcleo Celular/metabolismo , Proliferación Celular , Enzimas Ubiquitina-Conjugadoras/metabolismo , Transporte Activo de Núcleo Celular , Animales , Apoptosis , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Células COS , Línea Celular Tumoral , Supervivencia Celular , Chlorocebus aethiops , Citoplasma/metabolismo , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Microscopía Fluorescente , Mutación Puntual , Unión Proteica , Interferencia de ARN , Proteínas Recombinantes de Fusión/metabolismo , Transfección , Enzimas Ubiquitina-Conjugadoras/genética
16.
Int J Oncol ; 35(2): 387-91, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19578754

RESUMEN

CREB binding protein (CBP) is a transcriptional cofactor with intrinsic histone acetyl transferase activity (HAT). We have observed that CBP interacts with BRCA2 and mediates post-translational glycosylation of BRCA2. The binding of CBP to the amino-terminal region of BRCA2 is necessary for the glycosylation at residue 272 of BRCA2. Digestion with peptide N-glycosidase F indicates that the glycosylation of BRCA2 is N-linked. It is possible that this novel CBP-mediated post-translational N-glycosylation activity alters the conformation of CBP-interacting proteins, leading to regulation of gene expression, cell growth and differentiation.


Asunto(s)
Proteína BRCA2/metabolismo , Proteína de Unión a CREB/fisiología , Procesamiento Proteico-Postraduccional , Proteínas Reguladoras de la Apoptosis , Proteína de Unión a CREB/química , Línea Celular Tumoral , Femenino , Glicosilación , Humanos , Estructura Terciaria de Proteína
17.
J Cell Physiol ; 219(3): 634-41, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19170108

RESUMEN

BRCA1 is a tumor suppressor gene that is mutated in families with breast and ovarian cancer. Several BRCA1 splice variants are found in different tissues, but their subcellular localization and functions are poorly understood at the moment. We previously described BRCA1 splice variant BRCA1a to induce apoptosis and function as a tumor suppressor of triple negative breast, ovarian and prostate cancers. In this study we have analyzed the function of BRCA1 isoforms (BRCA1a and BRCA1b) and compared them to the wild-type BRCA1 protein using several criteria like studying expression in normal and tumor cells by RNase protection assays, subcellular localization/fractionation by immunofluorescence microscopy and Western blot analysis, transcription regulation of biological relevant proteins and growth suppression in breast cancer cells. We are demonstrating for the first time that ectopically expressed GFP-tagged BRCA1, BRCA1a, and BRCA1b proteins are localized to the mitochondria, repress ELK-1 transcriptional activity and possess antiproliferative activity on breast cancer cells. These results suggest that the exon 9, 10, and 11 sequences (aa 263-1365) which contain two nuclear localization signals, p53, Rb, c-Myc, gamma-tubulin, Stat, Rad51, Rad50 binding domains, angiopoietin-1 repression domain are not absolutely required for mitochondrial localization and growth suppressor function of these proteins. Since mitochondrial dysfunction is a hallmark of cancer, we can speculate that the mitochondrial localization of BRCA1 proteins may be functionally significant in regulating both the mitochondrial DNA damage as well as apoptotic activity of BRCA1 proteins and mislocalization causes cancer. J. Cell. Physiol. 219: 634-641, 2009. (c) 2009 Wiley-Liss, Inc.


Asunto(s)
Proteína BRCA1/metabolismo , Mitocondrias/metabolismo , Proteína Elk-1 con Dominio ets/metabolismo , Empalme Alternativo , Apoptosis , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Daño del ADN , Femenino , Genes BRCA1 , Inhibidores de Crecimiento/genética , Inhibidores de Crecimiento/metabolismo , Células HL-60 , Células HeLa , Humanos , Células K562 , Masculino , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Activación Transcripcional , Proteína Elk-1 con Dominio ets/genética
18.
Oncogene ; 23(42): 7087-94, 2004 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-15273724

RESUMEN

In the majority of Ewing's family tumors, chromosomal translocation t(11;22) leads to aberrant fusion of RNA-binding protein EWS with DNA-binding ETS transcriptional factor Fli-1. EWS-Fli-1 has altered the transcriptional activity and modulating its downstream target genes through this transcriptional activity is thought to be responsible for this tumor. We have previously shown that both EWS-Fli-1 and Fli-1 have antiapoptotic activity against several apoptotic inducers. Here, we show that the transcriptional activity of EWS-Fli-1 and Fli-1 is not essential for its antiapoptotic activity. We also demonstrate that EWS-Fli-1 and Fli-1 interact with CBP through its amino-terminal region and inhibit the CBP-dependent transcriptional activity of RXR. This activity appears to be independent of DNA-binding activity of EWS-Fli-1. Introduction of the dominant-negative form of CBP into Ewing's sarcoma cells sensitizes these cells against genotoxic or retinoic-acid induced apoptosis. These results suggest that the ability of EWS-Fli-1/Fli-1 to target transcriptional cofactor(s) and modulate apoptotic pathways may be responsible for its antiapoptotic and tumorigenic activities.


Asunto(s)
Apoptosis/fisiología , Neoplasias Óseas/genética , Supervivencia Celular/fisiología , Gelsolina/farmacología , Sarcoma de Ewing/genética , Actinas/genética , Secuencia de Bases , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 22/genética , Cartilla de ADN , Gelsolina/genética , Humanos , Proteínas de Microfilamentos , Reacción en Cadena de la Polimerasa/métodos , Receptores Citoplasmáticos y Nucleares/genética , Transactivadores , Transcripción Genética , Transfección , Translocación Genética
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