Effect of Antisense c-
            <i>raf</i>
            -1 on Tumorigenicity and Radiation Sensitivity of a Human Squamous Carcinoma

Kasid, Usha N.; Pfeifer, Andréa; Brennan, Terrence P.; Beckett, M.A.; Weichselbaum, R.R.; Dritschilo, Anatoly; Ge, Ming

doi:10.1126/science.2466340

Cited by 174 publications

(66 citation statements)

References 16 publications

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“…The molecular genetic factors that negate cell death and contribute to tumor progression can be attractive targets for therapeutic intervention (41,42). Current investigations in our laboratory are designed to examine the functional significance of SCC-S2 in cancer progression.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Novel Tumor Necrosis Factor-α-inducible Gene, SCC-S2, Containing the Consensus Sequence of a Death Effector Domain of Fas-associated Death Domain-like Interleukin- 1β-converting Enzyme-inhibitory Protein

Kumar¹,

Whiteside²,

Kasid³

2000

Journal of Biological Chemistry

123

135

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We report here the isolation and characterization of a novel tumor necrosis factor-␣ (TNF-␣)-inducible gene, SCC-S2. Based on the nucleotide sequence, the SCC-S2 open reading frame contains a sequence in the amino terminus that shows a significant homology to death effector domain II of cell death regulatory protein, Fasassociated death domain-like interleukin-1␤-converting enzyme-inhibitory protein (FLIP). Unlike FLIP, the SCC-S2 open reading frame contains only one death effector domain and lacks the carboxyl-terminal caspaselike homology domain, raising the possibility that SCC-S2 may be a novel member of the FLIP family. SCC-S2 mRNA expression is found in most normal tissues and malignant cells. The steady state level of SCC-S2 mRNA is significantly induced by TNF-␣ in different tumor cells (TNF-␣ at 20 ng/ml for 3 h: A549, ϳ2-9-fold; SKOV-3, ϳ3-fold; PCI-04A, ϳ3-6-fold). TNF-␣ treatment (100 ng/ml, 4 h) of HeLa cells transiently transfected with FLAG epitope-tagged SCC-S2 cDNA or expression vector alone led to an increase in the number of apoptotic cells as compared with the untreated counterpart. Interestingly, however, SCC-S2 transfectants revealed a significant decrease in the number of apoptotic cells as compared with the vector transfectants (p < 0.001). These data implicate a role of SCC-S2 as a negative mediator of apoptosis in certain cell types.Increasing evidence suggests that apoptosis requires activation of members of the interleukin-1␤-converting enzyme-like family of cysteine proteases, also known as caspases. The caspase activation appears to be triggered by some members of the TNFR 1 superfamily, including TNFR1 (p55/CD120a) and TNFR2 (p75/CD120b), and Fas/Apo-1 (CD95). TNF binds to TNFR1, and FasL binds to Fas. TNFR1 and Fas, also known as death receptors, are characterized by the presence of a cytoplasmic sequence motif called the death domain, which interacts with the death domain of the adaptor molecules FADD and TNFR-associated death domain, recruiting them to the membrane. TNFR-associated death domain interacts with FADD, and FADD, in turn, associates with an apical caspase, FLICE (caspase 8/MACH/Mch5), through death effector domains (DEDs) present at the carboxyl terminus of FADD and the amino terminus of FLICE, resulting in the assembly of a receptor-associated death-inducing signaling complex. Death-inducing signaling complex-associated FLICE signals proteolytic activation of downstream caspases, ultimately leading to apoptosis (reviewed in Ref. 1). FADD mutant containing only the death domain or FLICE containing two DEDs can act as a dominant negative inhibitor of apoptosis (2-4). Because ligand activation of a death receptor does not lead to apoptosis in all cell types, it has been suggested that natural cell death inhibitory molecules may exist in certain cells. Indeed, FLICE-inhibitory proteins (FLIP, CASH, I-FLICE, and FLAME-1) containing two sequence motifs with significant homology to DEDs have been identified (5-9). FLIPs contain two DEDs in the amino terminus and are repres...

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Section: Resultsmentioning

confidence: 99%

Identification of a Novel Tumor Necrosis Factor-α-inducible Gene, SCC-S2, Containing the Consensus Sequence of a Death Effector Domain of Fas-associated Death Domain-like Interleukin- 1β-converting Enzyme-inhibitory Protein

Kumar¹,

Whiteside²,

Kasid³

2000

Journal of Biological Chemistry

123

135

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“…Although the antisense technique has been widely used within the last few years, defining the best target sequence for antisense RNAs is still a challenge. However, the expression of selected genes has successfully been reduced by antisense RNAs complementary to the 5' translation start site and the coding region, as well as 3' untranslated regions (Wormington, 1986;Kasid et al, 1989). In our screening procedure, we observed a better mean inhibition (41.8%) of pro-cath-D secretion in clones transfected with the 535 bp fragment antisense cDNA construct as compared to the 26.5% mean reduction observed with clones transfected with the full-sequence antisense vector (Figure 1b).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells

et al. 2002

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Overexpression of cathepsin-D in primary breast cancer has been associated with rapid development of clinical metastasis. To investigate the role of this protease in breast cancer growth and progression to metastasis, we stably transfected a highly metastatic human breast cancer cell line, MDA-MB-231, with a plasmid containing either the full-length cDNA for cathepsin-D or a 535 bp antisense cathepsin-D cDNA fragment. Clones expressing antisense cathepsin-D cDNA that exhibited a 70 -80% reduction in cathepsin-D protein, both intra-and extracellularly compared to controls, were selected for further experiments. These antisense-transfected cells displayed a reduced outgrowth rate when embedded in a Matrigel matrix, formed smaller colonies in soft agar and presented a significantly decreased tumor growth and experimental lung metastasis in nude mice compared with controls. However, manipulating the cathepsin-D level in the antisense cells has no effect on their in vitro invasiveness. These studies demonstrate that cathepsin-D enhances anchorage-independent cell proliferation and subsequently facilitates tumorigenesis and metastasis of breast cancer cells. Our overall results provide the first evidence on the essential role of cathepsin-D in breast cancer, and support the development of a new cathepsin-D-targeted therapy.

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“…Activation of protooncogenes, such as H-Ras, and inactivation of tumor suppressor genes, including p53, are involved in HN carcinogenesis (Je eries and Foulkes, 2001). In addition to their role in oncogenesis, expression of transforming oncogenes has been shown to confer cellular radio-and/ or chemo-resistance (Kasid et al, 1989;Miller et al, 1993;Miura et al, 1997). The development of HNSCC is accompanied by genetic and epigenetic changes including loss of heterozygosity, gene inactivation by methylation, and/or gene ampli®cation, all of which can alter gene function (Bishop and Schiestl, 2001).…”

Section: Introductionmentioning

confidence: 99%

Identification of genes associated with head and neck carcinogenesis by cDNA microarray comparison between matched primary normal epithelial and squamous carcinoma cells

et al. 2002

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In order to identify genes involved in head and neck carcinogenesis, we compared the gene expression pro®le in matched primary normal epithelial cells and primary head and neck cancer cells from the same patients. A cDNA microarray analysis consisting of 12 530 human genes revealed signi®cant changes in the expression of 213 genes, with 91 genes being up-regulated and 122 being down-regulated. This comprehensive list of genes includes those associated with signal transduction (growth factors), cell structure, cell cycle, transcription, apoptosis, and cell ± cell adhesion. Further analysis of nine genes involved in cell ± cell interaction, using Western blot and/or reverse transcription (RT) ± PCR of four paired cell lines supported the reliability of our microarray analysis. More speci®cally, our study provides the ®rst evidence that claudin-7 and connexin 31.1 are down-regulated in head and neck squamous cell carcinomas (HNSCC) compared to normal cells. These ®ndings provide a large body of information regarding gene expression pro®les associated with head and neck carcinogenesis, and also represent a source of potential targets for HNSCC prevention and/or therapeutics.

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Effect of Antisense c- raf -1 on Tumorigenicity and Radiation Sensitivity of a Human Squamous Carcinoma

Cited by 174 publications

References 16 publications

Identification of a Novel Tumor Necrosis Factor-α-inducible Gene, SCC-S2, Containing the Consensus Sequence of a Death Effector Domain of Fas-associated Death Domain-like Interleukin- 1β-converting Enzyme-inhibitory Protein

Identification of a Novel Tumor Necrosis Factor-α-inducible Gene, SCC-S2, Containing the Consensus Sequence of a Death Effector Domain of Fas-associated Death Domain-like Interleukin- 1β-converting Enzyme-inhibitory Protein

Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells

Identification of genes associated with head and neck carcinogenesis by cDNA microarray comparison between matched primary normal epithelial and squamous carcinoma cells

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