The Experts below are selected from a list of 16713 Experts worldwide ranked by ideXlab platform
Dario C Altieri - One of the best experts on this subject based on the ideXlab platform.
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Survivin at a glance
Journal of Cell Science, 2019Co-Authors: Sally P Wheatley, Dario C AltieriAbstract:ABSTRACT Survivin (also known as BIRC5) is an evolutionarily conserved eukaryotic protein that is essential for cell division and can inhibit cell death. Normally it is only expressed in actively proliferating cells, but is upregulated in most, if not all cancers; consequently, it has received significant attention as a potential oncotherapeutic target. In this Cell Science at a Glance article and accompanying poster, we summarise our knowledge of Survivin 21 years on from its initial discovery. We describe the structure, expression and function of Survivin, highlight its interactome and conclude by describing anti-Survivin strategies being trialled.
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Survivin the inconvenient iap
Seminars in Cell & Developmental Biology, 2015Co-Authors: Dario C AltieriAbstract:Although technically a member of the Inhibitor of Apoptosis (IAP) gene family, Survivin has consistently defied assumptions, refuted predictions and challenged paradigms. Despite its more than 5500 citations currently in Medline, the biology of Survivin has remained fascinatingly complex, its exploitation in human disease, most notably cancer, tantalizing, and its regulation of cellular homeostasis unexpectedly far-reaching. An inconvenient outsider that resists schemes and dogmas, Survivin continues to hold great promise to unlock fundamental circuitries of cellular functions in health and disease.
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targeting Survivin in cancer
Cancer Letters, 2013Co-Authors: Dario C AltieriAbstract:With almost 4000 citations in Medline in a little over 10 years, Survivin has certainly kept scores of investigators busy worldwide. Tangible progress has been made in revealing the multiple functions of Survivin, uncovering their wirings as integrated cellular networks, and mapping their exploitation in virtually every human tumor, in vivo. Considering the normally long and excruciating timeline of oncology drug discovery, it is clearly a resounding success that a better understanding of Survivin biology has led to several clinical trials of Survivin-based therapeutics in cancer patients. However, the portfolio of Survivin antagonists available in the clinic remains small, pressing the need for a less rigid drug development approach to fully unlock the potential of this unique, albeit unconventional oncology drug target.
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endogenous tumor suppression mediated by pten involves Survivin gene silencing
Cancer Research, 2009Co-Authors: Minakshi Guha, Janet Plescia, Irwin Leav, Lucia R Languino, Dario C AltieriAbstract:Endogenous tumor suppression provides a barrier against oncogenesis, but the molecular requirements of this process are not well understood. Here, we show that the dual specificity phosphatase PTEN, a gene almost universally altered in human tumors, silences the expression of Survivin, an essential regulator of cell division and apoptosis in cancer. This pathway is independent of p53, involves active repression of Survivin gene transcription, and is mediated by direct occupancy of the Survivin promoter by FOXO1 and FOXO3a factors. Conditional deletion of PTEN in the mouse prostate causes deregulated induction of Survivin before full-blown transformation in vivo, whereas expression of Survivin and PTEN is inversely correlated in cancer patients. Therefore, silencing the Survivin gene is an essential requirement of endogenous PTEN tumor suppression.
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molecular mechanism of inhibition of Survivin transcription by the gc rich sequence selective dna binding antitumor agent hedamycin evidence of Survivin down regulation associated with drug sensitivity
Journal of Biological Chemistry, 2005Co-Authors: Xiang Ling, Dalin Pan, Pasha Apontes, Lei Song, Ping Liang, Dario C Altieri, Terry A BeermanAbstract:Expression of the antiapoptotic protein Survivin is associated with cancer cell viability and drug resistance. Thus, control of its expression in cancer cells has significant consequences for cancer therapeutics. Here we have shown that hedamycin, a GC-rich DNA binding drug, down-regulated Survivin expression. Using a series of Survivin promoter-luciferase constructs, we have identified an 86-bp GC-rich DNA element (-124 to -39) that mediates the ability of hedamycin to down-regulate Survivin expression. Furthermore, both in vivo foot-printing and in vitro gel mobility shift experiments revealed that hedamycin bound to a 21-bp GC-rich DNA element (-115 to -95) in the Survivin promoter. This drug-DNA interaction abrogated the binding of Sp-1 or Sp1-like proteins to the 21-bp cis-acting DNA element, and mutagenesis of this region consistently diminished Survivin promoter activity. Finally, down-regulation of Survivin transcription by hedamycin modulated the viability of cancer cells. These data suggest that abrogation of Sp-1 or Sp1-like protein binding to the 21-bp DNA element in the Survivin promoter contributes at least in part to the inhibitory effect of hedamycin on Survivin gene transcription. Drug-induced modulation of Survivin gene expression may provide novel approaches for cancer therapeutics.
Xiang Ling - One of the best experts on this subject based on the ideXlab platform.
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Cancer therapeutics using Survivin BIRC5 as a target: what can we do after over two decades of study?
Journal of Experimental & Clinical Cancer Research, 2019Co-Authors: Ieman Aljahdali, Xiang LingAbstract:Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of Survivin as a target for cancer therapeutics has remained a central goal of Survivin studies in the cancer field. Many studies have provided intriguing insight into Survivin’s functional role in cancers, thus providing promise for Survivin as a cancer therapeutic target. Despite this, moving Survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting Survivin. In this Review, we will first summarize the current Survivin mechanistic studies, and then review the status of Survivin cancer therapeutics, which is classified into five categories: (i) Survivin-partner protein interaction inhibitors, (ii) Survivin homodimerization inhibitors, (iii) Survivin gene transcription inhibitors, (iv) Survivin mRNA inhibitors and (v) Survivin immunotherapy. We will then provide our opinions on cancer therapeutics using Survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target Survivin for cancer therapy.
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forced expression of Survivin 2b abrogates mitotic cells and induces mitochondria dependent apoptosis by blockade of tubulin polymerization and modulation of bcl 2 bax and Survivin
Journal of Biological Chemistry, 2007Co-Authors: Xiang Ling, Qiuying Cheng, Jennifer D BlackAbstract:It has been previously shown that both Survivin and the Survivin splice variant Survivin-2B are localized in mitochondria. Whereas the mechanism involved in blockade of mitochondria-mediated apoptosis by Survivin has been extensively studied, the role of Survivin-2B in regulation of apoptosis has not been well defined. In the present study, we report that in addition to mitochondria, Survivin-2B is also localized in the microtubule organization center (MTOC) and, in contrast to other Survivin isoforms (i.e. Survivin and Survivin-ΔEx3), behaves as a proapoptotic molecule. We show that forced expression of Survivin-2B blocks tubulin polymerization, ablates mitotic cells, and induces mitochondria-dependent apoptosis. The mitochondria-mediated apoptosis induced by Survivin-2B was indicated by Smac release from mitochondria, activation of caspases 9 and 3, and loss of mitochondrial potential, while caspase-8 remained inactive. Further analysis of the mechanism for the mitochondria-associated events of apoptosis induced by forced expression of Survivin-2B revealed down-regulation of the pro-survival factor Bcl-2 and up-regulation of the pro-apoptotic factor Bax in mitochondria, while the apoptosis-inducing factor (AIF) remains unchanged. Our studies further showed that taxol (paclitaxel) treatment of cancer cells not only up-regulates Survivin but also down-regulates Survivin-2B and that forced expression of Survivin-2B sensitizes cells to taxol-induced cell growth inhibition and cell death, while silencing of endogenous Survivin-2B transcripts by Survivin-2B-specific siRNA made cells resistant to taxol treatment. These findings advance our current knowledge about Survivin-2B and may help to develop novel approaches for cancer treatment.
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Survivin study an update of what is the next wave
Journal of Cellular Physiology, 2006Co-Authors: Xiang LingAbstract:Studies on Survivin over the past 2-3 years have shown that Survivin possesses multiple subcellular localizations and is a multifunctional molecule involved in many aspects of cellular processes and/or behaviors. The subcellular localization and function of the Survivin splice variants, however, have not yet been well elucidated. We have, therefore, provided additional observations on several Survivin splice variants for further exploration. This review article will update the role of Survivin, and its splice variants in the mitosis/cell cycle, apoptosis, tumorigenesis, chemoprevention, drug/radiation resistance, and cancer therapeutics.
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molecular mechanism of inhibition of Survivin transcription by the gc rich sequence selective dna binding antitumor agent hedamycin evidence of Survivin down regulation associated with drug sensitivity
Journal of Biological Chemistry, 2005Co-Authors: Xiang Ling, Dalin Pan, Pasha Apontes, Lei Song, Ping Liang, Dario C Altieri, Terry A BeermanAbstract:Expression of the antiapoptotic protein Survivin is associated with cancer cell viability and drug resistance. Thus, control of its expression in cancer cells has significant consequences for cancer therapeutics. Here we have shown that hedamycin, a GC-rich DNA binding drug, down-regulated Survivin expression. Using a series of Survivin promoter-luciferase constructs, we have identified an 86-bp GC-rich DNA element (-124 to -39) that mediates the ability of hedamycin to down-regulate Survivin expression. Furthermore, both in vivo foot-printing and in vitro gel mobility shift experiments revealed that hedamycin bound to a 21-bp GC-rich DNA element (-115 to -95) in the Survivin promoter. This drug-DNA interaction abrogated the binding of Sp-1 or Sp1-like proteins to the 21-bp cis-acting DNA element, and mutagenesis of this region consistently diminished Survivin promoter activity. Finally, down-regulation of Survivin transcription by hedamycin modulated the viability of cancer cells. These data suggest that abrogation of Sp-1 or Sp1-like protein binding to the 21-bp DNA element in the Survivin promoter contributes at least in part to the inhibitory effect of hedamycin on Survivin gene transcription. Drug-induced modulation of Survivin gene expression may provide novel approaches for cancer therapeutics.
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molecular mechanism of inhibition of Survivin transcription by the gc rich sequence selective dna binding antitumor agent hedamycin evidence of Survivin down regulation associated with drug sensitivity
Journal of Biological Chemistry, 2005Co-Authors: Jianguo Wu, Xiang Ling, Pasha Apontes, Lei Song, Ping Liang, Dario C Altieri, Terry A Beerman, Fengzhi LiAbstract:Abstract Expression of the antiapoptotic protein Survivin is associated with cancer cell viability and drug resistance. Thus, control of its expression in cancer cells has significant consequences for cancer therapeutics. Here we have shown that hedamycin, a GC-rich DNA binding drug, down-regulated Survivin expression. Using a series of Survivin promoter-luciferase constructs, we have identified an 86-bp GC-rich DNA element (-124 to -39) that mediates the ability of hedamycin to down-regulate Survivin expression. Furthermore, both in vivo foot-printing and in vitro gel mobility shift experiments revealed that hedamycin bound to a 21-bp GC-rich DNA element (-115 to -95) in the Survivin promoter. This drug-DNA interaction abrogated the binding of Sp-1 or Sp1-like proteins to the 21-bp cis-acting DNA element, and mutagenesis of this region consistently diminished Survivin promoter activity. Finally, down-regulation of Survivin transcription by hedamycin modulated the viability of cancer cells. These data suggest that abrogation of Sp-1 or Sp1-like protein binding to the 21-bp DNA element in the Survivin promoter contributes at least in part to the inhibitory effect of hedamycin on Survivin gene transcription. Drug-induced modulation of Survivin gene expression may provide novel approaches for cancer therapeutics.
P J Guillou - One of the best experts on this subject based on the ideXlab platform.
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expression of Survivin a novel inhibitor of apoptosis and cell cycle regulatory protein in pancreatic adenocarcinoma
British Journal of Cancer, 2002Co-Authors: Abeezar I Sarela, Caroline S Verbeke, J Ramsdale, C L Davies, A F Markham, P J GuillouAbstract:Survivin is unique for its expression in human malignancies but not in normal adult cells. It has been implicated in sensitisation to chemotherapy and as a prognostic marker in several common cancers. Immunohistochemistry for Survivin, P53 and BCL-2 expression as well as cell proliferative index (Ki-67) and apoptosis index (TUNEL) was conducted on 52 pancreatic and 12 ampullary adenocarcinomas. Survivin was detected in the cytoplasm of carcinoma cells in 46 (88%) of pancreatic tumours. P53 and BCL-2 were detected in 54% and 12% of pancreatic tumours, respectively. Proliferative index was 26.2±10.5% and apoptosis index was 1.38±0.69%. Prevalence of Survivin expression was significantly higher in P53-positive than in P53-negative cases (P=0.05) but was not associated with BCL-2 expression. Incrementally higher weighted scores of Survivin expression were associated with increased proliferative index (P=0.001). Furthermore, there was linear correlation between increased proliferative index and higher apoptosis index (P<0.001). Surprisingly, higher scores of Survivin expression were associated with increased apoptosis index (P=0.007). Survival characteristics were not influenced by Survivin, P53 or BCL-2 expression, apoptosis index or proliferative index. Ampullary carcinoma showed Survivin expression in 83% of cases. However, unlike pancreatic carcinoma, there was no correlation between Survivin and P53 expression or proliferative index. In conclusion, Survivin is expressed in the majority of pancreatic adenocarcinomas and correlates with both cellular proliferation and apoptosis. Molecular manipulation of Survivin expression may enhance chemotherapy and radiation therapy for pancreatic cancer.
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expression of the antiapoptosis gene Survivin predicts death from recurrent colorectal carcinoma
Gut, 2000Co-Authors: Abeezar I Sarela, A F Markham, R C A Macadam, S M Farmery, P J GuillouAbstract:BACKGROUND/AIMS—Inhibition of programmed cell death (apoptosis) is associated with increased tumour aggressiveness, and expression of Survivin, an antiapoptosis gene, in colorectal carcinomas may provide important prognostic information. PATIENTS/METHODS—Expression of Survivin messenger RNA was evaluated by reverse transcription-polymerase chain reaction in 144 colorectal carcinomas and 86 adjacent histologically normal mucosa samples from patients for whom long term follow up data were available. RESULTS—Survivin transcripts were detected in a significantly greater proportion of carcinomas (63.5%) than normal mucosa samples (29.1%; p<0.001). The prevalence of Survivin expression was independent of advancing pathological stage. Death due to recurrent cancer following curative resection was predicted independently by tumour expression of Survivin (hazard ratio (HR) 2.60; 95% confidence interval (95% CI) 1.17-5.75) and lymph node metastases (HR 2.38; 95% CI 1.21-4.70). On stage wise analysis, the predictive value of Survivin expression was limited to patients with stage II colorectal carcinomas; those with Survivin negative tumours had a five year survival rate of 94.4% compared with 44.8% for patients with Survivin positive tumours (p=0.004, log rank test). CONCLUSION—In patients with stage II colorectal carcinomas, Survivin expression provides prognostic information that may have important therapeutic implications. Keywords: colorectal neoplasia; messenger RNA; polymerase chain reaction; prognosis; survival
Terry A Beerman - One of the best experts on this subject based on the ideXlab platform.
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molecular mechanism of inhibition of Survivin transcription by the gc rich sequence selective dna binding antitumor agent hedamycin evidence of Survivin down regulation associated with drug sensitivity
Journal of Biological Chemistry, 2005Co-Authors: Xiang Ling, Dalin Pan, Pasha Apontes, Lei Song, Ping Liang, Dario C Altieri, Terry A BeermanAbstract:Expression of the antiapoptotic protein Survivin is associated with cancer cell viability and drug resistance. Thus, control of its expression in cancer cells has significant consequences for cancer therapeutics. Here we have shown that hedamycin, a GC-rich DNA binding drug, down-regulated Survivin expression. Using a series of Survivin promoter-luciferase constructs, we have identified an 86-bp GC-rich DNA element (-124 to -39) that mediates the ability of hedamycin to down-regulate Survivin expression. Furthermore, both in vivo foot-printing and in vitro gel mobility shift experiments revealed that hedamycin bound to a 21-bp GC-rich DNA element (-115 to -95) in the Survivin promoter. This drug-DNA interaction abrogated the binding of Sp-1 or Sp1-like proteins to the 21-bp cis-acting DNA element, and mutagenesis of this region consistently diminished Survivin promoter activity. Finally, down-regulation of Survivin transcription by hedamycin modulated the viability of cancer cells. These data suggest that abrogation of Sp-1 or Sp1-like protein binding to the 21-bp DNA element in the Survivin promoter contributes at least in part to the inhibitory effect of hedamycin on Survivin gene transcription. Drug-induced modulation of Survivin gene expression may provide novel approaches for cancer therapeutics.
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molecular mechanism of inhibition of Survivin transcription by the gc rich sequence selective dna binding antitumor agent hedamycin evidence of Survivin down regulation associated with drug sensitivity
Journal of Biological Chemistry, 2005Co-Authors: Jianguo Wu, Xiang Ling, Pasha Apontes, Lei Song, Ping Liang, Dario C Altieri, Terry A Beerman, Fengzhi LiAbstract:Abstract Expression of the antiapoptotic protein Survivin is associated with cancer cell viability and drug resistance. Thus, control of its expression in cancer cells has significant consequences for cancer therapeutics. Here we have shown that hedamycin, a GC-rich DNA binding drug, down-regulated Survivin expression. Using a series of Survivin promoter-luciferase constructs, we have identified an 86-bp GC-rich DNA element (-124 to -39) that mediates the ability of hedamycin to down-regulate Survivin expression. Furthermore, both in vivo foot-printing and in vitro gel mobility shift experiments revealed that hedamycin bound to a 21-bp GC-rich DNA element (-115 to -95) in the Survivin promoter. This drug-DNA interaction abrogated the binding of Sp-1 or Sp1-like proteins to the 21-bp cis-acting DNA element, and mutagenesis of this region consistently diminished Survivin promoter activity. Finally, down-regulation of Survivin transcription by hedamycin modulated the viability of cancer cells. These data suggest that abrogation of Sp-1 or Sp1-like protein binding to the 21-bp DNA element in the Survivin promoter contributes at least in part to the inhibitory effect of hedamycin on Survivin gene transcription. Drug-induced modulation of Survivin gene expression may provide novel approaches for cancer therapeutics.
Fengzhi Li - One of the best experts on this subject based on the ideXlab platform.
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molecular mechanism of inhibition of Survivin transcription by the gc rich sequence selective dna binding antitumor agent hedamycin evidence of Survivin down regulation associated with drug sensitivity
Journal of Biological Chemistry, 2005Co-Authors: Jianguo Wu, Xiang Ling, Pasha Apontes, Lei Song, Ping Liang, Dario C Altieri, Terry A Beerman, Fengzhi LiAbstract:Abstract Expression of the antiapoptotic protein Survivin is associated with cancer cell viability and drug resistance. Thus, control of its expression in cancer cells has significant consequences for cancer therapeutics. Here we have shown that hedamycin, a GC-rich DNA binding drug, down-regulated Survivin expression. Using a series of Survivin promoter-luciferase constructs, we have identified an 86-bp GC-rich DNA element (-124 to -39) that mediates the ability of hedamycin to down-regulate Survivin expression. Furthermore, both in vivo foot-printing and in vitro gel mobility shift experiments revealed that hedamycin bound to a 21-bp GC-rich DNA element (-115 to -95) in the Survivin promoter. This drug-DNA interaction abrogated the binding of Sp-1 or Sp1-like proteins to the 21-bp cis-acting DNA element, and mutagenesis of this region consistently diminished Survivin promoter activity. Finally, down-regulation of Survivin transcription by hedamycin modulated the viability of cancer cells. These data suggest that abrogation of Sp-1 or Sp1-like protein binding to the 21-bp DNA element in the Survivin promoter contributes at least in part to the inhibitory effect of hedamycin on Survivin gene transcription. Drug-induced modulation of Survivin gene expression may provide novel approaches for cancer therapeutics.
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control of apoptosis and mitotic spindle checkpoint by Survivin
Nature, 1998Co-Authors: Fengzhi Li, Grazia Ambrosini, Janet Plescia, Simona Tognin, Pier Carlo Marchisio, Dario C AltieriAbstract:Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes1, acting to preserve homeostasis and developmental morphogenesis2. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry3 and controlling ploidy (chromosome number)4, the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein5,6, Survivin7, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, Survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics8. Disruption of Survivin–microtubule interactions results in loss of Survivin's anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that Survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of Survivin in cancer7 may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.