Abstract:
:Human telomerase is a unique reverse transcriptase that is expressed in multiple cancers, but not in the vast majority of normal cells. The enzyme is responsible for telomere protection and maintenance, and supports the proliferative immortality of cancer cells. Thus, it has been proposed that the specific inhibition of telomerase activity in tumors might have significant and beneficial therapeutic effects. To this goal we have designed, synthesized, and evaluated several oligonucleotide N3'-->P5' phosphoramidates as telomerase inhibitors. These oligonucleotides are complementary to the template region of the RNA domain of telomerase (hTR). The prepared compounds were evaluated in HME50-5E breast epithelial cells, where their effects on telomerase activity were determined using a cell-based telomerase (TRAP) assay at 24 as well as 72 h after exposure to compounds. The oligo-N3'-->P5' phosphoramidate inhibited telomerase activity in cells in the presence of the cellular up-take enhancer (FuGENE6) in a dose- and sequence-dependent manner, with IC(50) values of approximately 1 nM. Inhibition of telomerase activity by this compound without the lipid carrier was not efficient. However, the isosequential oligonucleotide N3'-->P5' thio-phosphoramidate was able to inhibit telomerase activity with or without lipid carriers at nM, or low-microM concentrations, respectively. This inhibition of telomerase activity in HME50-5E cells by the oligonucleotide thio-phosphoramidates was also sequence specific. Long-term treatment of the cells with 0.5 microM of FuGENE6 formulated 13-mer thio-phosphoramidates, fully complementary to hTR, resulted in gradual telomere shortening, followed by cellular senescence and apoptosis, as would be predicted for a telomerase inhibitor. The mismatched control compound had no effect on cell proliferation. The results suggest that the oligonucleotide N3'-->P5' phosphoramidates, and particularly thio-phosphoramidates, might be further developed as selective anti-telomerase reagents.
journal_name
Oncogenejournal_title
Oncogeneauthors
Herbert BS,Pongracz K,Shay JW,Gryaznov SMdoi
10.1038/sj.onc.1205064subject
Has Abstractpub_date
2002-01-21 00:00:00pages
638-42issue
4eissn
0950-9232issn
1476-5594journal_volume
21pub_type
杂志文章相关文献
ONCOGENE文献大全abstract::In order to assess the functional contribution of the human c-myc promoter region in the expression of the c-myc gene, transgenic mouse lines containing a bacterial lac Z gene encoding beta-galactosidase under the control of the human c-myc protooncogene promoter were generated. Transgenic mouse embryos heterozygous f...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1995-06-15 00:00:00
abstract::The serine threonine checkpoint kinase 2 (CHK2) is a critical protein involved in the DNA damage-response pathway, which is activated by phosphorylation inducing cellular response such as DNA repair, cell-cycle regulation or apoptosis. Although CHK2 activation mechanisms have been amply described, very little is known...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2015.495
更新日期:2016-08-18 00:00:00
abstract::We compared the regulation of gamma-glutamyl transferase (gamma GT) and glutathione-S-transferase-P (GST-P) expression in rat liver epithelial cells (228 cells) and a line derived from them (C5 cells) by stable transfection with a metallothionein-activated ras fusion gene (MTrasT24). Earlier studies demonstrated that ...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1989-06-01 00:00:00
abstract::High-grade serous carcinoma, accounts for up to 70% of all ovarian cases. Furin, a proprotein convertase, is highly expressed in high-grade serous carcinoma of ovarian cancer patients, and its expression is even higher in tumor omentum than in normal omentum, the preferred site of ovarian cancer metastasis. The proteo...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-020-1194-7
更新日期:2020-04-01 00:00:00
abstract::In a previous work we provided preliminary evidence of the existence of a putative tumor suppressor gene region on the distal part of chromosome 4 in gamma-radiation-induced T-cell lymphomas of (C57BL/6J x RF/J) F1 hybrid mice. This region, named as TLSR2 (Thymic Lymphoma Suppressor Region 2), was located centered at ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202009
更新日期:1998-08-20 00:00:00
abstract::The angiogenic peptide adrenomedullin (ADM) has been implicated as a mediator of the increased risk of endometrial hyperplasia and cancer resulting from the use of tamoxifen for the treatment and prevention of breast cancer. ADM has been shown to be induced by tamoxifen in the endometrium and to be a growth factor for...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1205374
更新日期:2002-04-25 00:00:00
abstract::Lin28b is an RNA-binding protein that inhibits biogenesis of let-7 microRNAs. LIN28B is overexpressed in diverse cancers, yet a specific role in the molecular pathogenesis of colon cancer has to be elucidated. We have determined that human colon tumors exhibit decreased levels of mature let-7 isoforms and increased ex...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2011.131
更新日期:2011-10-06 00:00:00
abstract::KLF6, a ubiquitously expressed Krüppel-like transcription factor, is frequently inactivated in human cancer and has significant roles in cellular proliferation, apoptosis, differentiation and development. A key mechanism of KLF6-mediated growth suppression is through p53-independent transactivation of p21. Several can...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2012.457
更新日期:2013-09-19 00:00:00
abstract::The Neuregulins and their receptors, the ErbB/HER subfamily of receptor tyrosine kinases, have critical roles in animal physiology, and their deregulation is frequent in cancer. Here we report the identification of the guanine nucleotide exchange factor, phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2010.489
更新日期:2011-03-03 00:00:00
abstract::High frequencies of allelic loss on the short arm of chromosome 3 in small cell lung cancer (SCLC) and a number of other tumors suggest the existence of a tumor suppressor gene(s) within the deleted regions. Two small cell lung cancer lines, NCI H740 and GLC20, have been described which have homozygous deletions in th...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1996-12-05 00:00:00
abstract::We previously reported that overexpression of the 24 kDa basic fibroblast factor (or FGF-2) isoform provides protection from the cytotoxic effect of ionizing radiation (IR). DNA double-strand breaks (DSB), the IR-induced lethal lesions, are mainly repaired in human cells by non-homologous end joining system (NHEJ). NH...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1205838
更新日期:2002-09-19 00:00:00
abstract::Inactivation of tumor-suppressor genes is one of the key hallmarks of a tumor. Unlike other tumor-suppressor genes, p53 is inactivated by missense mutations in half of all human cancers. It has become increasingly clear that the resulting mutant p53 proteins do not represent only the mere loss of wild-type p53 tumor s...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1210296
更新日期:2007-04-02 00:00:00
abstract::Mutations in VHL underlie von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome with several subtypes depending on the risk of developing certain combination of classic features, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma and pheochromocytoma. Although numerous potential substrates and f...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2017.338
更新日期:2018-01-11 00:00:00
abstract::A variety of factors cooperate to regulate neovessel formation and persistence. Proangiogenic growth factors have remained an area of intense interest due to their capacity to promote endothelial cell (EC) proliferation and to initiate the angiogenic program. These growth factors are associated with increased cell sur...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1207110
更新日期:2003-12-08 00:00:00
abstract::CBF beta-SMMHC is expressed from the inv(16) chromosome in M4Eo AML. Mice lacking CBF subunits or expressing the CBF beta-SMMHC or AML1-ETO oncoproteins failed to develop definitive hematopoiesis. To investigate these effects on hematopoiesis, we expressed CBF beta-SMMHC from the metallothionein promoter, in both 32D ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201305
更新日期:1997-09-01 00:00:00
abstract::Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in neuroblastoma, a devastating pediatric cancer of the sympathetic nervous system. Germline and somatically acquired ALK aberrations induce increased autophosphorylation, constitutive ALK activation and increased downstream signaling....
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2011.647
更新日期:2012-11-15 00:00:00
abstract::Among surface molecules expressed on endothelial cells, endoglin (CD105) is emerging as a prime vascular target for antiangiogenetic cancer therapy. CD105 is a cell membrane glycoprotein mainly expressed on endothelial cells and overexpressed on tumor-associated vascular endothelium, which functions as an accessory co...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1206813
更新日期:2003-09-29 00:00:00
abstract::Dysregulation of cellular signaling pathways can lead to colon cancer. However, research on the key signaling effectors or regulators in colon carcinogenesis is limited. Casein kinase-2 interacting protein-1 (CKIP-1; also known as PLEKHO1) is crucial during adult bone formation and is a promising drug target for osteo...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2013.340
更新日期:2014-07-10 00:00:00
abstract::A growing body of literature suggests that the ubiquitously expressed Src family kinases (Src, Fyn and Yes) are required for agents such as platelet-derived growth factor (PDGF) to stimulate DNA synthesis. Yet Klinghoffer and colleagues recently presented evidence that fibroblasts derived from mice null for Src, Fyn a...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1203608
更新日期:2000-06-01 00:00:00
abstract::The RET proto-oncogene encodes a functional receptor tyrosine kinase (Ret) for the Glial cell line Derived Neurotrophic Factor (GDNF). RET is involved in several neoplastic and non-neoplastic human diseases. Oncogenic activation of RET is detected in human papillary thyroid tumours and in multiple endocrine neoplasia ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201778
更新日期:1998-05-14 00:00:00
abstract::We have shown earlier that overexpression of Calreticulin (CRT) contributed to a poor prognosis for patients with esophageal squamous cell carcinoma (ESCC). Here, we have shown an important role of CRT in tumorigenesis through enhancing cell motility and anoikis resistance. SiRNA-mediated knockdown of CRT caused impai...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2009.237
更新日期:2009-10-22 00:00:00
abstract::Neuroblastoma is a childhood tumor thought to arise through improper differentiation of neural crest cells. Increased N-Myc expression in neuroblastoma indicates highly malignant disease and poor patient prognosis. N-myc enhances cell growth, insulin-like growth factor type I receptor (IGF-IR) expression, and tumorige...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206362
更新日期:2003-05-01 00:00:00
abstract::The IGF2 gene, which encodes a growth factor, is subject to genomic imprinting. The frequently observed loss of IGF2 imprinting in a variety of tumors has been suggested to contribute to neoplasia. Since these reports have not documented the imprinting status of IGF2 at the cellular level, it cannot be excluded that t...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201501
更新日期:1998-01-08 00:00:00
abstract::Thrombospondin-1 (TSP-1) is an endogenous inhibitor of angiogenesis whose expression suppresses tumor growth in vivo. Like many angiogenesis-related genes, TSP-1 expression is tightly controlled by various mechanisms, but there is little data regarding the contribution of post-transcriptional processing to this regula...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2012.464
更新日期:2013-09-12 00:00:00
abstract::p66(Shc), an isoform of Shc adaptor proteins, is shown to mediate various signals, including cellular stress. However, little is known about its involvement in carcinogenesis. We previously showed that p66(Shc) protein level is upregulated by steroid hormones in human carcinoma cells and is higher in prostate cancer (...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208852
更新日期:2005-11-03 00:00:00
abstract::Here we describe the identification of a novel vertebrate-specific centrosome/spindle pole-associated protein (CSPP) involved in cell-cycle regulation. The protein is predicted to have a tripartite domain structure, where the N- and C-terminal domains are linked through a coiled-coil mid-domain. Experimental analysis ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208267
更新日期:2005-02-10 00:00:00
abstract::Aurora kinases are known to play a key role in maintaining mitotic fidelity, and overexpression of aurora kinases has been noted in various tumors. Overexpression of aurora kinase activity is thought to promote cancer development through a loss of centrosome or chromosome number integrity. Here we observed augmentatio...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208293
更新日期:2005-02-03 00:00:00
abstract::DNA adducts associated with tobacco smoking could provide a marker of biologically effective dose of tobacco carcinogens and improve individual cancer risk prediction. A significant number of clinical and epidemiologic studies have reported associations of increased DNA adduct levels with the occurrence of the prevale...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1205799
更新日期:2002-10-21 00:00:00
abstract::Cell cycle checkpoints and tumor suppressor gene functions appear to be required for the maintenance of a stable genome in proliferating cells. In this study chromosomal destabilization was monitored in relation to telomere structure, lifespan control and G2 checkpoint function. Replicative senescence was inactivated ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201711
更新日期:1998-04-09 00:00:00
abstract::Cell cycle modulation of cyclin A expression is due to the periodic relief of a transcriptional repression mediated by a bipartite negative DNA regulatory region. The 5' element (Cell Cycle Responsive Element: CCRE; cell Cycle Dependent Element: CDE) is clearly occupied in a cyclic manner in vivo, whereas the 3' eleme...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1203017
更新日期:1999-11-04 00:00:00