Smad4 deficiency in cervical carcinoma cells

Baldus, Stephan; Schwarz, Elisabeth; Lohrey, Claudia; Zapatka, Marc; Landsberg, Stephanie; Hahn, Stephan A.; Schmidt, Dietmar; Dienes, Hans Peter; Schmiegel, Wolff; Schwarte-Waldhoff, Irmgard

doi:10.1038/sj.onc.1208235

Cited by 36 publications

(37 citation statements)

References 36 publications

(44 reference statements)

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“…Taken together, these results indicate that Bax is critical for the induction of apoptotic cell death upon E6 inhibition. To exclude that the crucial connection between E6 and Bax is specific for HPV18-positive HeLa cells, we also performed clonogenic survival assays in HPV16-positive MRI-H-186 cells (Baldus et al, 2005). Similarly as observed for HeLa cells, targeted inhibition of HPV16 E6 by RNAi also resulted in a strong inhibition of the colony formation capacity in MRI-H-186 cells, which again was counteracted by concomitant silencing of bax expression (Table 1).…”

Section: Inhibition Of Bax Activation Is Crucial For the Antiapoptotimentioning

confidence: 86%

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Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein

et al. 2006

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Oncogenic types of human papillomaviruses (HPVs) cause cervical cancer in humans. The antiapoptotic viral E6 gene has been identified as a key factor for maintaining the viability of HPV-positive cancer cells. Although E6 has the potential to modulate many apoptosis regulators, the crucial apoptotic pathway blocked by endogenous E6 in cervical cancer cells remained unknown. Using RNA interference (RNAi), here, we show that targeted inhibition of E6 expression in cervical cancer cells leads to the transcriptional stimulation of the PUMA promoter, in a p53-dependent manner. This is linked to the activation and translocation of Bax to the mitochondrial membrane, cytochrome c release into the cytosol, and activation of caspase-3, in a PUMA-dependent manner. Moreover, inhibition of Bax expression by RNAi efficiently reverts the apoptotic phenotype, which results from inhibition of E6 expression. Thus, interference with the p53/PUMA/ Bax cascade is crucial for the antiapoptotic function of the viral E6 oncogene in HPV-positive cancer cells.

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Section: Inhibition Of Bax Activation Is Crucial For the Antiapoptotimentioning

confidence: 86%

“…HPV16-positive MRI-H-186 cervical carcinoma cells (Baldus et al, 2005) were maintained in RPMI-1640 medium supplemented with 10% FCS. Plasmids were transfected by calcium phosphate co-precipitation (Chen and Okayama, 1987).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein

et al. 2006

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“…1 Although a number of studies have investigated the expression status and alterations in the canonical TGF-b signaling (Smad) pathway, the role of Smad signaling in the progression of cervical cancer remains unclear. 3,10,11,24 In this study, we investigated whether decreased Smad2 and Smad4 protein expression in primary cervical cancers was associated with molecular alterations at 18q21.1, mutations in the functional domains of Smad2 and Smad4 or hypermethylation, and we assessed the biological relevance of decreased Smad2 and Smad4 expression.…”

Section: Discussionmentioning

confidence: 99%

“…10 It should be noted that of these cell lines, one cell line was derived from a lymph node metastases (HT-3) and two other cell lines (C4-I and C4-II) were derived from the same patient. The origin of the fourth cell line was not specified.…”

Section: Discussionmentioning

confidence: 99%

“…5,8 Also, Smad2 mutations have been found in colorectal cancer. 9 For cervical cancer, Smad4 mutations were reported in cervical cancer cell lines 10 and a Smad2 mutation in a cervical tumor has been described. 11 In addition to LOH and gene mutations, other mechanisms such as CpG methylation of the Smad promoter may play a role in downregulation of Smad expression.…”

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confidence: 99%

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Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival

et al. 2008

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Alterations in transforming growth factor-b signaling, due to a decrease in Smad2 and especially Smad4 expression, has primarily been reported in pancreatic and colorectal cancers, although loss of the chromosomal region 18q21.1, containing the loci of Smad2 and Smad4, is among the most frequent molecular alterations in cervical cancer. The aim of our study was to investigate whether decreased Smad2 and Smad4 protein expression in primary cervical cancers is associated with molecular alterations at 18q21.1, mutations in the functional domains of Smad2 and Smad4 or hypermethylation, and to assess the biological relevance of decreased Smad2 and Smad4 expression. Subsequently, Smad2, Smad4 and p21 protein expression was determined by immunohistochemistry in 117 primary cervical carcinomas, assembled in a tissue array. Smad signaling was shown to be associated with p21 mRNA expression. All the tumors expressed Smad2 or Smad4. Weak cytoplasmic Smad2 or weak cytoplasmic Smad4 expression could not be attributed to loss of heterozygosity at 18q21.1. Despite weak/moderate Smad2 expression and absent nuclear Smad4 expression, the coding regions of the functional MH1 and MH2 domains of Smad2 and Smad4 were unchanged, as assessed by sequence analysis. The Smad4 promoter region was unmethylated in tumor samples with weak/moderate cytoplasmic Smad4 expression. Remarkably, both weak cytoplasmic Smad4 expression and absent nuclear Smad4 expression significantly correlated with poor disease-free (P ¼ 0.003 and P ¼ 0.003, respectively) and overall 5-year survival (P ¼ 0.003 and P ¼ 0.010, respectively). Our findings support the hypothesis that Smad4 is a target molecule for functional inactivation in cervical cancer.

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Kinetic studies on free radical polymerization of acrylonitrile, initiated by chloramine‐T/hydrogen peroxide redox system

Mahadevaiah

Demappa

2006

J of Applied Polymer Sci

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The Kinetics of polymerization of Acrylonitrile initiated by chloramine-T/H 2 O 2 Redox System was studied in aqueous medium in the temperature range of 35-508C. The effects of variations such as [Monomer], [CAT], [H 2 O 2 ], temperature, and chloramine-T disappearance (ÀR m ) were measured. The effect of some water-miscible organic solvents and surfactants on the rate of polymerization was investigated. The polymerization process is initiated by the free radical arising from oxidation of H 2 O 2 by chloramine-T and terminated by the mutual combination of the growing polymer radicals. Based on the kinetic results, a suitable reaction scheme is proposed and discussed for the various rates of polymerization and thermodynamic parameters were evaluated.

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Smad4 deficiency in cervical carcinoma cells

Cited by 36 publications

References 36 publications

Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein

Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein

Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival

Kinetic studies on free radical polymerization of acrylonitrile, initiated by chloramine‐T/hydrogen peroxide redox system

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