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T Littlewood

Publications and source records attributed to T Littlewood.

32 records · Page 2Linked to original sources
PubMed1999

Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion.

The protooncogene c-myc regulates cell growth, differentiation, and apoptosis, and its aberrant expression is frequently observed in human cancer. However, the consequences of activating c-Myc in an adult tissue, in which these cellular processes are part of normal homeostasis, remain unknown. In order to achieve this, we have targeted expression of a switchable form of the c-Myc protein to the skin epidermis, a well characterized homeostatic tissue. We show that activation of c-MycER in adult suprabasal epidermis rapidly triggers proliferation and disrupts differentiation of postmitotic keratinocytes. Sustained activation of c-Myc is sufficient to induce papillomatosis together with angiogenesis--changes that resemble hyperplastic actinic keratosis, a commonly observed human precancerous epithelial lesion. All these premalignant changes spontaneously regress upon deactivation of c-MycER.

Animals↗
PubMed1999

Conceptualisation of diarrhoea in Nepal.

Nepal has a small and isolated population, but one which has received considerable aid in relation to health. Infant mortality rates are high. One of the main causes of infant death is diarrhoeal disease. Mothers can distinguish different types of diarrhoea and effect different treatments.

Adult↗
PubMed1998

A matter of life and cell death.

In multicellular organisms, mutations in somatic cells affecting critical genes that regulate cell proliferation and survival cause fatal cancers. Repair of the damage is one obvious option, although the relative inconsequence of individual cells in metazoans means that it is often a "safer" strategy to ablate the offending cell. Not surprisingly, corruption of the machinery that senses or implements DNA damage greatly predisposes to cancer. Nonetheless, even when oncogenic mutations do occur, there exist potent mechanisms that limit the expansion of affected cells by suppressing their proliferation or triggering their suicide. Growing understanding of these innate mechanisms is suggesting novel therapeutic strategies for cancer.

Animals↗
PubMed1997

Induction of TNF-sensitive cellular phenotype by c-Myc involves p53 and impaired NF-kappaB activation.

Normal fibroblasts are resistant to the cytotoxic action of tumor necrosis factor (TNF), but are rendered TNF-sensitive upon deregulation of c-Myc. To assess if oncoproteins induce the cytotoxic TNF activity by modulating TNF signaling, we investigated the TNF-elicited signaling responses in fibroblasts containing a conditionally active c-Myc protein. In association with cell death, c-Myc impaired TNF-induced activation of phospholipase A2, JNK protein kinase and cell survival-signaling-associated NF-kappaB transcription factor complex. The TNF-induced death of mouse primary fibroblasts expressing deregulated c-Myc was inhibited by transient overexpression of the p65 subunit of NF-kappaB, which increased NF-kappaB activity in the cells. Unlike other TNF-induced signals, TNF-induced accumulation of the wild-type p53 mRNA and protein was not inhibited by c-Myc. TNF, with c-Myc, induced apoptosis in mouse primary fibroblasts but only weakly in p53-deficient primary fibroblasts. The C-terminal domain of p53, which is a transacting dominant inhibitor of wild-type p53, failed to inhibit apoptosis by c-Myc and TNF, suggesting that the cell death was not dependent on the transcription-activating function of p53. Taken together, the present findings show that the cytotoxic activity of TNF towards oncoprotein-expressing cells involves p53 and an impaired signaling for survival in such cells.

3T3 Cells↗
PubMed1997

Resistance to p53-mediated growth arrest and apoptosis in Hep 3B hepatoma cells.

Mutations in the tumor suppressor p53 are a common event in hepatocellular carcinoma (HCC). Because HCCs typically occur in livers with chronic injury and impaired function, we have explored the role of wild-type p53 in regulating the growth and differentiation of Hep 3B hepatoma cells, a p53-negative line derived from a liver cancer. Stable Hep 3B cell lines were generated in which inducible p53 was introduced using either a temperature-sensitive mutant (p53val135) or a tamoxifen-regulated p53-estrogen receptor chimera (p53-mERtm-pBabepuro). In both cell lines, induction of transcriptionally active p53 was confirmed by assessing several p53 targets: Mdm2 protein, p21waf1 mRNA and protein, and the cyclin G promoter. Despite marked induction of p21waf1, cells with active p53 failed to undergo growth arrest, which is probably due to the presence of a non-functional retinoblastoma protein (pRb) in these cells. Apoptosis also was not observed, even after prolonged (48 h) serum starvation or exposure to cisplatinum. Lack of apoptosis was correlated with unchanged bax mRNA levels following p53 induction. Additionally, albumin mRNA levels remained unchanged, and there was no change in basal transactivation of a reporter containing the promoter of the haptoglobin gene, encoding an acute phase protein. This suggests that growth arrest may be required to promote liver-specific gene expression. Overall, our data demonstrate that introduction of transcriptionally active p53 does not alter the malignant, dedifferentiated phenotype of Hep 3B hepatoma cells. Hence, not all cancer cells are equally responsive to the re-activation of wild-type 53. The ability of a cancer cell to undergo p53-mediated phenotypic alterations may depend on the retention of functional downstream effector pathways.

Apoptosis↗
PubMed1997

Presentation and survival of patients with severe renal failure and myeloma.

We reviewed the clinical features and outcome of 56 patients with myeloma and severe renal failure managed in a single institution over a 15-year period. Renal failure was recognized within 2 months of the diagnosis of myeloma in 75% of patients, and was the initial presentation of myeloma in 50%. Patients were staged by the Durie and Salmon classification. Light-chain and IgD myeloma accounted for 46% of cases, and Bence-Jones proteinuria was identified in > 90%. In 43%, a potential precipitant of renal failure was identified, usually hypercalcaemia or a non-steroidal anti-inflammatory agent. A preserved corrected calcium at presentation was characteristic (2.40 +/- 0.15 mmol/l, n = 42), even after excluding those with hypercalcaemia requiring specific intervention (n = 14, 2.76 +/- 0.51; p < 0.01): this finding in patients with unexplained acute renal failure should alert clinicians to the possibility of myeloma. Forty-seven patients (84%) required dialysis. Only seven (15%) ever regained renal function. Median survival (all patients) was 8 months. One-third died within 3 months of referral and one-third survived > 1 year. Hypoalbuminaemia and reduced platelet count at presentation were associated with reduced survival, but hypercalcaemia, infection, dialysis, (urgent or long-term), and dialysis modality were not. Chemotherapy was associated with increased survival, but progression of myeloma and infection were the two most frequent causes of death. Severe renal failure was associated with advanced myeloma stage and light-chain/IgD paraproteinaemia. Survival was related to severity of myeloma and not requirement for dialysis per se.

Adult↗
PubMed1994

Site-specific modulation of c-Myc cotransformation by residues phosphorylated in vivo.

c-Myc is a nuclear phosphoprotein which binds DNA as a heterodimer with Max. We have identified two in vivo phosphorylation sites, Thr58 and Ser62, within a domain highly conserved among all Myc family members. Thr58 is mutated in several viral forms of the protein and constitutes a mutational hot-spot in Burkitt's lymphoma. Members of the GSK-3 and MAP kinase families, but not CKII, specifically phosphorylated these sites in vitro. The effect of these phosphorylation sites on Myc function was assessed by cotransformation of primary rat embryo fibroblasts with Ras. Mutagenesis of Thr58 to alanine potentiated focus formation, whereas substitution of Ser62 severely inhibited transformation. Mutation of both residues restored wild-type activity. These data suggest acute, post-translational modulation of Myc via phosphorylation of a conserved region previously implicated in transactivation, transformation and autorepression.

Amino Acid Sequence↗
PubMed1992

Down-regulation of cellular proto-oncogenes during inhibition of rat parotid acinar cell proliferation.

The role of cell surface galactosyltransferase in mediating isoproterenol-induced parotid gland hypertrophy and hyperplasia was examined in rat parotid gland acinar cells. Introduction of the transferase modifier, alpha-lactalbumin, or galactosyltransferase-associated kinase inhibitor trifluoperazine, into beta-agonist-treated rats prevented acinar cell proliferation as determined by [3H]thymidine incorporation after 96 h of treatment. However, [3H]thymidine incorporation into DNA after 24 h of treatment, with injection of a combination of isoproterenol/alpha-lactalbumin or isoproterenol/trifluoperazine, was similar to injections of isoproterenol alone; suggesting that acinar cells could be stimulated to undergo a single round of DNA synthesis. Northern blot analysis of myc and fos expression followed a similar pattern of down-regulation to control levels after 96 h but not after 24 h. Hybridization with erb B showed little change with proliferation, confirming previous observations on protein levels of the EGF-receptor in acinar cells. Western blot analysis of nuclear protein expression of myc revealed that isoproterenol caused an increase in a 62-kDa protein which was again down-regulated with inhibition of cell proliferation. Analysis of protein levels of Rb110 protein showed no change in protein level in the nucleus with cell proliferation, but did show an associated increase in protein phosphorylation in response to growth stimulation.

Animals↗
PubMed1992

Abnormal haemoglobin electrophoresis caused by BW 12C.

BW 12C, a substituted benzaldehyde, stabilises haemoglobin in the oxy-conformation and has attracted interest as an anti-sickling agent. The drug causes a left shift in the oxygen saturation curve and may induce tumour anoxia and enhance the effect of cytotoxic drugs. During clinical trials in patients with cancer abnormal bands on haemoglobin electrophoretic strips were observed. This made correct diagnosis of abnormal haemoglobins impossible. Solubility tests for sickling disorders (Itano) also proved unreliable.

Adenocarcinoma↗
PubMed1987

Reduced in vitro erythroid progenitor cell growth in bronchial cancer.

Peripheral blood and bone marrow were studied in 21 men with disseminated untreated bronchial cancer in an attempt to define abnormalities of erythropoiesis associated with the development of anaemia. Haemoglobin concentration at or below 13 g/dl was present in 13 cases. Marrow morphology was normal in all cases except one, in which small numbers of tumour cells were found. Clonal assay of erythroid progenitors showed a significant decrease in the number of BFU-E (p = 0.03) and CFU-E (p = 0.01) compared with cultures from normal marrow (12 subjects). The growth of granulocyte and macrophage progenitors (GM-CFCs) was similar in patients with bronchial cancer and normal subjects. When normal marrow was incubated in the presence of serum from bronchial cancer patients, no inhibitory factors could be detected either for BFU-E or CFU-E growth. In all patients circulating T8 numbers were significantly raised (p = 0.0002). Consequently, the median T4:T8 ratio in blood was 1.2, and this was significantly lower than the ratio of 1.7 found in 20 normal subjects (p = 0.036). In 18 patients the bone marrow T4:T8 ratio of 1.1 was significantly lower than the ratio of 2.9 found in seven normal subjects (p = 0.04). Total blood white cell counts, neutrophils, and monocyte numbers were also increased (p = 0.0001; p = 0.0001; p = 0.002).

Aged↗
PubMed1986

Characterization of the human c-myc protein using antibodies prepared against synthetic peptides.

Synthetic peptides with amino acid sequences based on inferred sequences encoded by the human c-myc proto-oncogene have been used as immunogens to produce polyclonal and monoclonal antibodies. These peptide-specific antibodies have then been used to identify the intact human c-myc protein. By immunoprecipitation and immunoblotting analysis we have defined the human c-myc protein as a phosphoprotein with an apparent molecular mass of 62 kDa on a sodium dodecyl sulphate-polyacrylamide gel. The protein is present in both normal and transformed cells but the steady-state levels of p62c-myc are elevated in the transformed cells by comparison with normal ones. We have used our anti-c-myc peptide antibodies to study the subcellular localization of p62c-myc. We find the protein to be loosely associated with cell nuclei by an interaction which is highly sensitive to variations in ionic strength within the physiological range. In response to in vitro or in vivo heat-shock the protein becomes sequestered in an insoluble complex associated with the nucleus. This complex contains a discrete subset of nuclear proteins, of which p62c-myc is a member. Immunofluorescence microscopy of p62c-myc shows it to be localized in a defined and previously unobserved subnuclear structure. A role for p62c-myc as an intracellular messenger is suggested.

Amino Acid Sequence↗
PubMed1986

Adult acute lymphoblastic leukaemia presenting with bone marrow aplasia.

We report two adult patients who presented with bone marrow aplasia and latterly were diagnosed to have acute lymphoblastic leukaemia (ALL). Although the aplastic presentation of ALL in childhood is well documented it has not been previously reported in adult ALL. The mechanism of this presentation is unclear. In one of our patients folate deficiency appears to have been the cause.

Acute Disease↗
PubMedDate not supplied

Risk group definition in children with acute myeloid leukemia by calculating individual risk factors on the basis of a multivariate stepwise Cox regression analysis.

To define risk groups in children with acute myeloid leukaemia (AML), we conducted a multivariate stepwise Cox regression analysis of three consecutive multicentre studies in East Germany. The total number of patients was 240, but cytogenetics and remission status on day 15 were routinely investigated only in the most recent study, AML-III/93 (78 patients). We derived an equation to calculate individual risk factors, determined those risk factors for all patients of study AML-III/93 and divided them into three groups with 26 patients in each. The variables in the equation were: WBC, FAB-type, auer rods, cytogenetics and response status on day 15. The event-free survival was 80% in the low risk, 55% in the intermediate risk and 15% in the high risk group. Our results strongly suggest that calculating individual risk factors on the basis of a multivariate stepwise Cox regression analysis is a useful tool in defining risk groups.

Child↗