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Dario C Altieri - One of the best experts on this subject based on the ideXlab platform.
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molecular dependence of estrogen receptor negative breast cancer on a notch survivin signaling axis
Cancer Research, 2008Co-Authors: Christopher M Raskett, Igor Prudovsky, Dario C AltieriAbstract:Despite progress in the management of breast cancer, the molecular underpinnings of clinically aggressive subtypes of the disease are not well-understood. Here, we show that activation of Notch developmental signaling in estrogen receptor (ER)–negative breast cancer cells results in direct transcriptional up-regulation of the Apoptosis Inhibitor and cell cycle regulator survivin. This response is associated with increased expression of survivin at mitosis, enhanced cell proliferation, and heightened viability at cell division. Conversely, targeting Notch signaling with a peptidyl γ-secretase Inhibitor suppressed survivin levels, induced Apoptosis, abolished colony formation in soft agar, and inhibited localized and metastatic tumor growth in mice, without organ or systemic toxicity. In contrast, ER+ breast cancer cells, or various normal cell types, were insensitive to Notch stimulation. Therefore, ER− breast cancer cells become dependent on Notch-survivin signaling for their maintenance, in vivo . Therapeutic targeting of this pathway may be explored for individualized treatment of patients with clinically aggressive, ER− breast cancer. [Cancer Res 2008;68(13):5273–81]
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survivin expression in oral squamous cell carcinoma
British Journal of Cancer, 2003Co-Authors: Lorenzo Lo Muzio, Giuseppe Pannone, Stefania Staibano, Michele D Mignogna, Corrado Rubini, Maria Addolorata Mariggio, Maurizio Procaccini, Francesca Ferrari, G De Rosa, Dario C AltieriAbstract:A series of 110 cases of oral squamous cell carcinoma (SCC) together with six lymph node and one distant metastatic lesions was analysed for expression of survivin, a recent Apoptosis Inhibitor, by immunohistochemistry and Western blotting. In total, 91 cases (82.7%) of carcinoma and all metastasis (seven cases, 100%) were positive for survivin expression, with weighted survivin scores ranging from 1 to 4. In contrast, normal oral epithelium did not express survivin. There was no significant correlation between survivin expression and age, sex, tumour size, the presence of lymph node and distant metastases. Survivin expression was increased in poorly differentiated tumours, even if differences were not statistically significant. In contrast, when analysed for prognostic significance, patients with low survivin expression had statistically significant better survival rates than the group with high survivin expression (P<0.05). These data suggest that survivin expression may identify cases of oral SCC with more aggressive and invasive phenotype.
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cancer gene therapy using a survivin mutant adenovirus
Journal of Clinical Investigation, 2001Co-Authors: Mehdi Mesri, Nathan R Wall, Richard W Kim, Dario C AltieriAbstract:We have constructed a replication-deficient adenovirus encoding a nonphosphorylatable Thr(34)-->Ala mutant of the Apoptosis Inhibitor survivin (pAd-T34A) to target tumor cell viability in vitro and in vivo. Infection with pAd-T34A caused spontaneous Apoptosis in cell lines of breast, cervical, prostate, lung, and colorectal cancer. In contrast, pAd-T34A did not affect cell viability of proliferating normal human cells, including fibroblasts, endothelium, or smooth muscle cells. Infection of tumor cells with pAd-T34A resulted in cytochrome c release from mitochondria, cleavage of approximately 46-kDa upstream caspase-9, processing of caspase-3 to the active subunits of approximately 17 and 19 kDa, and increased caspase-3 catalytic activity. When compared with chemotherapeutic regimens, pAd-T34A was as effective as taxol and considerably more effective than adriamycin in induction of tumor cell Apoptosis and enhanced taxol-induced cell death. In three xenograft breast cancer models in immunodeficient mice, pAd-T34A suppressed de novo tumor formation, inhibited by approximately 40% the growth of established tumors, and reduced intraperitoneal tumor dissemination. Tumors injected with pAd-T34A exhibited loss of proliferating cells and massive Apoptosis by in situ internucleosomal DNA fragmentation. These data suggest that adenoviral targeting of the survivin pathway may provide a novel approach for selective cancer gene therapy.
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angiopoietin 1 inhibits endothelial cell Apoptosis via the akt survivin pathway
Journal of Biological Chemistry, 2000Co-Authors: Dario C Altieri, Andreas Papapetropoulos, David J Fulton, Keyvan Mahboubi, Robert G Kalb, Daniel S Oconnor, Fengzhi Li, William C SessaAbstract:Abstract A productive angiogenic response must couple to the survival machinery of endothelial cells to preserve the integrity of newly formed vessels. Angiopoietin-1 (Ang-1) is an endothelium-specific ligand essential for embryonic vascular stabilization, branching morphogenesis, and post-natal angiogenesis, but its contribution to endothelial cell survival has not been completely elucidated. Here we show that Ang-1 acting via the Tie 2 receptor induces phosphorylation of the survival serine-threonine kinase, Akt (or protein kinase B). This is associated with up-regulation of the Apoptosis Inhibitor, survivin, in endothelial cells and protection of endothelium from death-inducing stimuli. Moreover, dominant negative survivin negates the ability of Ang-1 to protect cells from undergoing Apoptosis. The activation of anti-apoptotic pathways mediated by Akt and survivin in endothelial cells may contribute to Ang-1 stabilization of vascular structures during angiogenesis, in vivo.
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expression and targeting of the Apoptosis Inhibitor survivin in human melanoma
Journal of Investigative Dermatology, 1999Co-Authors: Douglas Grossman, Jennifer M Mcniff, Dario C AltieriAbstract:The newly described Apoptosis Inhibitor survivin is expressed in many human cancers and appears to play a critical part in both Apoptosis regulation and cell cycle progression. Its potential role in malignant melanoma is unknown. In a panel of 30 malignant melanomas, survivin was strongly expressed in all cases (15 of 15) of metastatic malignant melanomas and 13 of 15 cases of invasive malignant melanomas by immunohistochemistry. In invasive malignant melanomas, survivin was also expressed in the in-situ component of the lesion. Survivin expression was found in all cases (11 of 11) of nevi, but not in melanocytes in sections of normal skin. The Apoptosis Inhibitor bcl-2 was expressed in 26 of 30 cases, but generally at lower levels than that of infiltrating lymphocytes. The mitotic index, as assessed by MIB-1 staining, was consistently higher in metastatic than invasive malignant melanomas. Assessment of apoptotic index by in situ end-labeling revealed extremely low rates of Apoptosis in most malignant melanomas. Survivin expression by western blotting was detected in four human metastatic malignant melanoma cell lines but not in cultured normal human melanocytes. Transfection of both YUSAC-2 and LOX malignant melanoma cells with green fluorescence protein-conjugated survivin anti-sense or green fluorescence protein-conjugated survivin dominant negative mutant (Cys85Ala) resulted in increased Apoptosis in the absence of other genotoxic stimuli. Two-color flow cytometry confirmed that YUSAC-2 cells transfected with survivin anti-sense expressed less endogenous survivin and exhibited an increased fraction of cells with sub-G1 DNA content. These data demonstrate that Apoptosis inhibition by survivin may participate in the onset and progression of malignant melanomas, and suggest that therapeutic targeting of survivin may be beneficial in patients with recurrent or metastatic disease.
Céline Gélinas - One of the best experts on this subject based on the ideXlab platform.
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regulation of death receptor expression and trail apo2l induced Apoptosis by nf κb
Nature Cell Biology, 2001Co-Authors: Rajani Ravi, Gauri. C. Bedi, Laura W. Engstrom, Qinwen Zeng, Bijoyesh Mookerjee, Céline Gélinas, Ephraim J. Fuchs, Atul BediAbstract:TRAIL (tumour-necrosis factor-related Apoptosis ligand or Apo2L) triggers Apoptosis through engagement of the death receptors TRAIL-R1 (also known as DR4) and TRAIL-R2 (DR5). Here we show that the c-Rel subunit of the transcription factor NF-κB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the Inhibitory protein IκBα or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-κB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-κB also increases expression of the Apoptosis Inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-κB by blocking activation of the IκB kinase complex reduces Bcl-xL expression and sensitizes tumour cells to TRAIL-induced Apoptosis. The ability to induce death receptors or Bcl-xL may explain the dual roles of NF-κB as a mediator or Inhibitor of cell death during immune and stress responses.
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the rel nf κb family directly activates expression of the Apoptosis Inhibitor bcl xl
Molecular and Cellular Biology, 2000Co-Authors: Cailin Chen, Céline Gélinas, Leonard C EdelsteinAbstract:The transcription factors of the Rel/NF-kappaB family are key regulators of immune and inflammatory responses and contribute to lymphocyte proliferation, survival, and oncogenesis. The absolute correlation between the antiapoptotic and oncogenic activities of the Rel/NF-kappaB oncoprotein v-Rel emphasizes the importance of characterizing the death antagonists under NF-kappaB control. Our recent finding that the prosurvival Bcl-2 homolog Bfl-1 (also called A1) is a direct transcriptional target of NF-kappaB raised the issue of whether NF-kappaB is a specific or global regulator of death antagonists in the Bcl-2 family. Here, we demonstrate that NF-kappaB differentially regulates the expression of particular Bcl-2-related death Inhibitors and that it directly activates the expression of Bcl-x(L). While Bcl-x(L) was significantly upregulated by c-Rel and RelA, Bcl-2 was not. Importantly, stimuli that activate endogenous NF-kappaB factors also upregulated bcl-x gene expression and this effect was antagonized by an Inhibitor of NF-kappaB activity. The expression of bcl-x suppressed Apoptosis in the presence or absence of NF-kappaB activity. Functional analysis of the bcl-x promoter demonstrated that it is directly controlled by c-Rel. These results establish that NF-kappaB directly regulates the expression of distinct prosurvival factors in the Bcl-2 family, such as Bcl-x(L) and Bfl-1/A1. These findings raise the possibility that some of these factors may contribute to oncogenesis associated with aberrant Rel/NF-kappaB activity.
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the rel nf kappab family directly activates expression of the Apoptosis Inhibitor bcl x l
Molecular and Cellular Biology, 2000Co-Authors: Cailin Chen, Céline Gélinas, Leonard C EdelsteinAbstract:The transcription factors of the Rel/NF-kappaB family are key regulators of immune and inflammatory responses and contribute to lymphocyte proliferation, survival, and oncogenesis. The absolute correlation between the antiapoptotic and oncogenic activities of the Rel/NF-kappaB oncoprotein v-Rel emphasizes the importance of characterizing the death antagonists under NF-kappaB control. Our recent finding that the prosurvival Bcl-2 homolog Bfl-1 (also called A1) is a direct transcriptional target of NF-kappaB raised the issue of whether NF-kappaB is a specific or global regulator of death antagonists in the Bcl-2 family. Here, we demonstrate that NF-kappaB differentially regulates the expression of particular Bcl-2-related death Inhibitors and that it directly activates the expression of Bcl-x(L). While Bcl-x(L) was significantly upregulated by c-Rel and RelA, Bcl-2 was not. Importantly, stimuli that activate endogenous NF-kappaB factors also upregulated bcl-x gene expression and this effect was antagonized by an Inhibitor of NF-kappaB activity. The expression of bcl-x suppressed Apoptosis in the presence or absence of NF-kappaB activity. Functional analysis of the bcl-x promoter demonstrated that it is directly controlled by c-Rel. These results establish that NF-kappaB directly regulates the expression of distinct prosurvival factors in the Bcl-2 family, such as Bcl-x(L) and Bfl-1/A1. These findings raise the possibility that some of these factors may contribute to oncogenesis associated with aberrant Rel/NF-kappaB activity.
Yu Wang - One of the best experts on this subject based on the ideXlab platform.
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expression of the Apoptosis Inhibitor livin in colorectal adenoma carcinoma sequence correlations with pathology and outcome
Tumor Biology, 2014Co-Authors: Yu Wang, Bin Zhou, Weihan Zhang, J T Guan, R Wang, L Yang, Q J Xia, Zongguang Zhou, Xiaofeng SunAbstract:The Inhibitor of Apoptosis family member livin is expressed in several types of cancer but not in most benign tissues, and it has been considered to be a poor prognostic mark in various malignancies. However, livin expression and its prognostic relevance have not been evaluated in colorectal adenoma-carcinoma sequence. In this study, we analyzed the difference of livin expression among normal mucosa, adenoma, and adenocarcinoma and investigated the relationship of livin expression in carcinomas with clinicopathological variables using immunohistochemistry and real-time reverse transcription-PCR. We observed that the expression of livin protein was mainly present on base of colorectal crypts in adenoma and throughout the epithelium in carcinoma, whereas did not present in accompanying normal mucosa, and the expression of livin messenger RNA (mRNA) in adenocarcinomas was significantly higher than in adenomas and in normal mucosa (P = 0.001, respectively), whereas, compared with normal mucosa, the expression level of livin mRNA was up-regulated in adenomas but no significant difference (P = 0.196). We also found that the expression levels of livin mRNA in rectal cancer was significantly higher than those in colonic cancer, and livin mRNA expression was strongly related to colorectal cancer invasive depth but not to clinical tumor stage, differentiation, lymph node metastasis, tumor morphological category and pathological type, and patient’s age and gender. These findings support the possibility that the livin gene may play a role in colorectal tumorigenesis, and increased expression of livin mRNA may serve as a new target for colorectal cancer treatment.
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profiling microrna expression in hepatocellular carcinoma reveals microrna 224 up regulation and Apoptosis Inhibitor 5 as a microrna 224 specific target
Journal of Biological Chemistry, 2008Co-Authors: Yu Wang, Alvin T C Lee, Joel Z I, Jingbo Wang, Jianwei Ren, Yuchen Yang, Erwin Tantoso, London L P J Ooi, Patrick Tan, Caroline G L LeeAbstract:Like other cancers, aberrant gene regulation features significantly in hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) were recently found to regulate gene expression at the post-transcriptional/translational levels. The expression profiles of 157 miRNAs were examined in 19 HCC patients, and 19 up-regulated and 3 down-regulated miRNAs were found to be associated with HCC. Putative gene targets of these 22 miRNAs were predicted in silico and were significantly enriched in 34 biological pathways, most of which are frequently dysregulated during carcinogenesis. Further characterization of microRNA-224 (miR-224), the most significantly up-regulated miRNA in HCC patients, revealed that miR-224 increases apoptotic cell death as well as proliferation and targets Apoptosis Inhibitor-5 (API-5) to inhibit API-5 transcript expression. Significantly, miR-224 expression was found to be inversely correlated with API-5 expression in HCC patients (p < 0.05). Hence, our findings define a true in vivo target of miR-224 and reaffirm the important role of miRNAs in the dysregulation of cellular processes that may ultimately lead to tumorigenesis.
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profiling microrna expression in hepatocellular carcinoma reveals microrna 224 up regulation and Apoptosis Inhibitor 5 as a microrna 224 specific target
Journal of Biological Chemistry, 2008Co-Authors: Yu Wang, Alvin T C Lee, Joel Z I, Jingbo Wang, Jianwei Ren, Yuchen Yang, Erwin Tantoso, London L P J Ooi, Patrick Tan, Caroline G L LeeAbstract:Like other cancers, aberrant gene regulation features significantly in hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) were recently found to regulate gene expression at the post-transcriptional/translational levels. The expression profiles of 157 miRNAs were examined in 19 HCC patients, and 19 up-regulated and 3 down-regulated miRNAs were found to be associated with HCC. Putative gene targets of these 22 miRNAs were predicted in silico and were significantly enriched in 34 biological pathways, most of which are frequently dysregulated during carcinogenesis. Further characterization of microRNA-224 (miR-224), the most significantly up-regulated miRNA in HCC patients, revealed that miR-224 increases apoptotic cell death as well as proliferation and targets Apoptosis Inhibitor-5 (API-5) to inhibit API-5 transcript expression. Significantly, miR-224 expression was found to be inversely correlated with API-5 expression in HCC patients (p
Caroline G L Lee - One of the best experts on this subject based on the ideXlab platform.
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profiling microrna expression in hepatocellular carcinoma reveals microrna 224 up regulation and Apoptosis Inhibitor 5 as a microrna 224 specific target
Journal of Biological Chemistry, 2008Co-Authors: Yu Wang, Alvin T C Lee, Joel Z I, Jingbo Wang, Jianwei Ren, Yuchen Yang, Erwin Tantoso, London L P J Ooi, Patrick Tan, Caroline G L LeeAbstract:Like other cancers, aberrant gene regulation features significantly in hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) were recently found to regulate gene expression at the post-transcriptional/translational levels. The expression profiles of 157 miRNAs were examined in 19 HCC patients, and 19 up-regulated and 3 down-regulated miRNAs were found to be associated with HCC. Putative gene targets of these 22 miRNAs were predicted in silico and were significantly enriched in 34 biological pathways, most of which are frequently dysregulated during carcinogenesis. Further characterization of microRNA-224 (miR-224), the most significantly up-regulated miRNA in HCC patients, revealed that miR-224 increases apoptotic cell death as well as proliferation and targets Apoptosis Inhibitor-5 (API-5) to inhibit API-5 transcript expression. Significantly, miR-224 expression was found to be inversely correlated with API-5 expression in HCC patients (p < 0.05). Hence, our findings define a true in vivo target of miR-224 and reaffirm the important role of miRNAs in the dysregulation of cellular processes that may ultimately lead to tumorigenesis.
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profiling microrna expression in hepatocellular carcinoma reveals microrna 224 up regulation and Apoptosis Inhibitor 5 as a microrna 224 specific target
Journal of Biological Chemistry, 2008Co-Authors: Yu Wang, Alvin T C Lee, Joel Z I, Jingbo Wang, Jianwei Ren, Yuchen Yang, Erwin Tantoso, London L P J Ooi, Patrick Tan, Caroline G L LeeAbstract:Like other cancers, aberrant gene regulation features significantly in hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) were recently found to regulate gene expression at the post-transcriptional/translational levels. The expression profiles of 157 miRNAs were examined in 19 HCC patients, and 19 up-regulated and 3 down-regulated miRNAs were found to be associated with HCC. Putative gene targets of these 22 miRNAs were predicted in silico and were significantly enriched in 34 biological pathways, most of which are frequently dysregulated during carcinogenesis. Further characterization of microRNA-224 (miR-224), the most significantly up-regulated miRNA in HCC patients, revealed that miR-224 increases apoptotic cell death as well as proliferation and targets Apoptosis Inhibitor-5 (API-5) to inhibit API-5 transcript expression. Significantly, miR-224 expression was found to be inversely correlated with API-5 expression in HCC patients (p
Albert Abad - One of the best experts on this subject based on the ideXlab platform.
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a novel anti Apoptosis gene re expression of survivin messenger rna as a prognosis marker in non small cell lung cancers
Journal of Clinical Oncology, 1999Co-Authors: Mariano Monzo, Rafael Rosell, Enriqueta Felip, Julio Astudillo, Jose Javier Sanchez, Jose Maestre, Cristina Martin, Albert Font, Agusti Barnadas, Albert AbadAbstract:PURPOSE: The survivin gene is a novel Apoptosis Inhibitor, related to the baculovirus gene, which is believed to play a pivotal role in fetal development and in cancer. We hypothesised that survivin would be expressed in tumors of patients with non–small-cell lung cancer (NSCLC), and we attempted to determine the influence of survivin re-expression on clinical outcome in patients with up to stage IIIA NSCLC who had undergone radical surgery. METHODS: We designed a reverse transcriptase polymerase chain reaction (RT-PCR) assay to study the expression of the survivin gene in 83 NSCLC tumor samples and compared the results with relevant clinical and pathologic data. RESULTS: The RT-PCR identified survivin gene transcript in 71 (85.5%) of the tumor samples and in only 10 (12%) of the paired, histopathologically normal lung samples. There was no relationship between histologic subtype (squamous v nonsquamous) and survivin gene expression. The 12 patients without survivin expression had significantly better ove...
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a novel anti Apoptosis gene re expression of survivin messenger rna as a prognosis marker in non small cell lung cancers
Journal of Clinical Oncology, 1999Co-Authors: Mariano Monzo, Rafael Rosell, Enriqueta Felip, Julio Astudillo, Jose Javier Sanchez, Jose Maestre, Cristina Martin, Albert Font, Agusti Barnadas, Albert AbadAbstract:PURPOSE: The survivin gene is a novel Apoptosis Inhibitor, related to the baculovirus gene, which is believed to play a pivotal role in fetal development and in cancer. We hypothesised that survivin would be expressed in tumors of patients with non–small-cell lung cancer (NSCLC), and we attempted to determine the influence of survivin re-expression on clinical outcome in patients with up to stage IIIA NSCLC who had undergone radical surgery. METHODS: We designed a reverse transcriptase polymerase chain reaction (RT-PCR) assay to study the expression of the survivin gene in 83 NSCLC tumor samples and compared the results with relevant clinical and pathologic data. RESULTS: The RT-PCR identified survivin gene transcript in 71 (85.5%) of the tumor samples and in only 10 (12%) of the paired, histopathologically normal lung samples. There was no relationship between histologic subtype (squamous v nonsquamous) and survivin gene expression. The 12 patients without survivin expression had significantly better ove...