Search PubMed⌕ Search

Biomedical subjects

C Bonner

Publications and source records attributed to C Bonner.

8 recordsLinked to original sources
PubMed2006

Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway.

The proteasome has emerged as a novel target for antineoplastic treatment of hematological malignancies and solid tumors, including those of the central nervous system. To identify cell death pathways activated in response to inhibition of the proteasome system in cancer cells, we treated human SH-SY5Y neuroblastoma cells with the selective proteasome inhibitor (PI) epoxomicin (Epoxo). Prolonged exposure to Epoxo was associated with increased levels of poly-ubiquitinylated proteins and p53, release of cytochrome c from the mitochondria, and activation of caspases. Analysis of global gene expression using high-density oligonucleotide microarrays revealed that Epoxo triggered transcriptional activation of the two Bcl-2-homology domain-3-only (BH3-only) genes p53 upregulated modulator of apoptosis (PUMA) and Bim. Subsequent studies in PUMA- and Bim-deficient cells indicated that Epoxo-induced caspase activation and apoptosis was predominantly PUMA-dependent. Further characterization of the transcriptional response to Epoxo in HCT116 human colon cancer cells demonstrated that PUMA induction was p53-dependent; with deficiency in either p53 or PUMA significantly protected HCT116 cells against Epoxo-induced apoptosis. Our data suggest that p53 activation and the transcriptional induction of its target gene PUMA play an important role in the sensitivity of cancer cells to apoptosis induced by proteasome inhibition, and imply that antineoplastic therapies with PIs might be especially useful in cancers with functional p53.

Apoptosis↗
PubMed2006

Downregulation of protein kinase B/Akt-1 mediates INS-1 insulinoma cell apoptosis induced by dominant-negative suppression of hepatocyte nuclear factor-1alpha function.

AIMS/HYPOTHESIS: Inactivating mutations in Tcf1, which encodes the transcription factor hepatocyte nuclear factor (HNF)-1alpha, cause maturity-onset diabetes of the young-3. We have previously shown that a dominant-negative mutant (DN-HNF-1alpha) renders INS-1 insulinoma cells sensitive to the mitochondrial apoptosis pathway, but the underlying alterations in signal transduction remain unknown. MATERIALS AND METHODS: Using a reverse tetracycline-dependent transactivator system, DN-HNF-1alpha-induced apoptosis was assessed by immunoblotting and caspase assays. Alterations in AKT1 kinase/protein kinase B (AKT1) survival signalling during DN-HNF-1alpha-induced apoptosis were investigated by phospho-specific immunodetection and transient transfection experiments. RESULTS: Induction of DN-HNF-1alpha caused significant changes in the activation-specific phosphorylation status of AKT1 that were preceded by a downregulation of Ins1 gene transcription. Phosphorylation of AKT1 at Ser473 was dramatically reduced after 36 to 48 h of DN-HNF-1alpha induction and coincided with maximal apoptosis activation. Overexpression of a constitutively active mutant of Akt1 rescued INS-1 cells from DN-HNF-1alpha-induced apoptosis, while ectopic expression of a dominant-negative mutant mimicked the effect of DN-HNF-1alpha on apoptosis activation. Pharmacological suppression of growth factor survival signalling through administration of the phosphatidylinositol-3 kinase (PI-3K) inhibitor wortmannin accelerated the induction of apoptosis by DN-HNF-1alpha. CONCLUSIONS/INTERPRETATION: These data suggest that a decrease in PI-3K/AKT1 survival signalling mediates DN-HNF-1alpha-induced apoptosis in insulin-secreting cells.

Androstadienes↗
PubMed2001

Analysis of outbreaks of infectious intestinal disease in Ireland: 1998 and 1999.

Surveillance of general outbreaks of infectious gastroenteritis was introduced in 1998 by the Food Safety Authority of Ireland (FSAI), in co-operation with the eight health boards. A total of 67 general outbreaks of gastroenteritis in Ireland were reported to the FSAI in 1998 and 1999. Over 1900 people were ill as a result of these outbreaks. Four percent required hospitalisation and there were two deaths. The duration of the outbreaks varied between one day and 38 days. Salmonellae (44%) and small round structured viruses (SRSV) (12%) were the most commonly reported pathogens. In 25% of the outbreaks the aetiology was unknown. The commonest settings were restaurants, hotels and take-aways, which accounted for 45% (30/67) of all outbreaks. Sixteen percent of all outbreaks occurred in hospitals and residential institutions. Over half of the outbreaks were reported to be foodborne, 63% of which were due to various serotypes of Salmonella enterica. Eggs were implicated as the vehicle of infection in 13% of all outbreaks. An infected food handler was identified in almost one third of outbreaks, although it could not be established if this had contributed directly to the outbreak.

Cross Infection↗
PubMed1982

Pituitary-adrenal function in rats chronically exposed to cold.

Exposure to cold for 2 weeks was used to assess the effects of a sustained stimulus on pituitary-adrenal function in male rats. The diurnal peak in plasma and adrenal corticosterone was advanced by 4 h during the first 24 h of exposure to cold but returned to its usual time (2000 h) by the next day. Plasma ACTH and corticosterone levels were generally greater at all times during the 24-h cycle in animals exposed to cold for up to 2 weeks, with the greatest increase occurring consistently at the time of peak. When rats exposed to cold for 1 week were returned to a normal 24 C environment, plasma corticosterone tended to increase. Plasma ACTH and plasma and adrenal corticosterone responses to a superimposed acute provocative stimulus (ip saline injection) were faster, greater, and more sustained in rats exposed to cold for 3 or 7 days. Similarly, the compensatory adrenal hypertrophy response to unilateral adrenalectomy was greater in cold-exposed rats. Such animals were also more resistant to pituitary-adrenal suppression by prednisolone. In contrast, there was no change in the sensitivity of the adrenal to exogenous ACTH. The results suggest that chronic exposure to cold causes a sustained activation of central mechanisms that regulate pituitary ACTH secretion as well as extra-pituitary mechanisms that regulate adrenal size; it reduces the effectiveness of negative feedback mechanisms, but does not alter those involved in the regulation of adrenal rhythmicity or adrenal sensitivity to ACTH.

Adrenal Glands↗
PubMedDate not supplied

The effect of eye closure upon the pathological vestibular spontaneous nystagmus.

In the course of one year (September 1973 to September 1974) a total of 784 patients were examined with nystagmography. We were dealing with patients who consulted us for reasons of equilibrium disturbances, sensori-neural hearing loss and/or tinnitus. In 200 patients we observed a definite vestibular spontaneous nystagmus (SN) in supine position. Ocular pendular nystagmus was eliminated. On the basis of these 200 electronystagmographic recordings, the effect of eye closure upon the pathological spontaneous nystagmus was analysed. According to the statistical mean value, spontaneous nystagmus with open eyes in darkness was stimulated by eye closure. Further evaluation revealed, however, that 24% of our patients showed spontaneous nystagmus exclusively with open eyes in darkness, 30% only with closed eyes. Nevertheless, the occurrence of spontaneous nystagmus with either open or closed eyes in darkness, or in both conditions, does not permit topodiagnostic conclusions. The possibility of nystagmus inhibition by eye closure must be considered when the case history indicates a vestibular disturbance but a spontaneous nystagmus with closed eyes in absent in the electronystagmography. The clinical observations in one patient are described in detail for example. To exclude errors, one should search for a spontaneous nystagmus following the necessary examination behind Frenzel's glasses-in case of nystagmography-by closed as well as by opened eyes in darkness.

Adolescent↗
PubMedDate not supplied

Defining roles.

Explore the source record for details and available documents.

British Columbia↗