Two periods of sensitivity to mutagens in induced Mel cells with different outcomes

Foresti, M.; Paoletti, Iole; Mele, Franca; Geraci, G.

doi:10.1016/s0027-5107(96)00242-4

Cited by 3 publications

(1 citation statement)

References 11 publications

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“…Excluding tumours due to the effect of external factors such as viruses [5], stem cells appear to be good candidates for tumour origination because they are able to duplicate and have not reached a final and stable genetic stage and because their genomes must undergo reprogramming to express the proper differentiated phenotype. In line with this hypothesis is the finding that cultured tumour mouse erythroleukemia cells are particularly sensitive to mutations in specific periods during erythroid differentiation [6], [7], [8]. Random mutations are expected to occur more frequently in nucleotide positions that are not relevant for molecular functions and in genes not necessary to express a differentiated phenotype.…”

Section: Introductionmentioning

confidence: 95%

Evidence of Genetic Instability in Tumors and Normal Nearby Tissues

Geraci

D'Elia²,

Gaudio³

et al. 2010

PLoS ONE

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BackgroundComprehensive analyses have recently been performed on many human cancer tissues, leading to the identification of a number of mutated genes but providing no information on the variety of mutations present in each of them. This information is of interest to understand the possible origin of gene mutations that cause tumors.Methodology/Principal FindingsWe have analyzed the sequence heterogeneity of the transcripts of the human HPRT and G6PD single copy genes that are not considered tumor markers. Analyses have been performed on different colon cancers and on the nearby histologically normal tissues of two male patients. Several copies of each cDNA, which were produced by cloning the RT-PCR-amplified fragments of the specific mRNA, have been sequenced. Similar analyses have been performed on blood samples of two ostensibly healthy males as reference controls. The sequence heterogeneity of the HPRT and G6PD genes was also determined on DNA from tumor tissues. The employed analytical approach revealed the presence of low-frequency mutations not detectable by other procedures. The results show that genetic heterogeneity is detectable in HPRT and G6PD transcripts in both tumors and nearby healthy tissues of the two studied colon tumors. Similar frequencies of mutations are observed in patient genomic DNA, indicating that mutations have a somatic origin. HPRT transcripts show genetic heterogeneity also in healthy individuals, in agreement with previous results on human T-cells, while G6PD transcript heterogeneity is a characteristic of the patient tissues. Interestingly, data on TP53 show little, if any, heterogeneity in the same tissues.Conclusions/SignificanceThese findings show that genetic heterogeneity is a peculiarity not only of cancer cells but also of the normal tissue where a tumor arises.

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Section: Introductionmentioning

confidence: 95%

Evidence of Genetic Instability in Tumors and Normal Nearby Tissues

Geraci

D'Elia²,

Gaudio³

et al. 2010

PLoS ONE

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A short low-level exposure to metavanadate during a cell cycle-specific interval of time is sufficient to permanently derange the differentiative properties of Mel cells

Foresti

Scippa²,

Mele³

et al. 2001

Mutagenesis

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Mouse erythroleukemia (Mel) cells have a cell cycle-dependent high sensitivity to chemical and physical mutagens. This report shows that a 5 h exposure to 0.1 or 0.01 microg/ml metavanadate during the initial period of erythroid differentiation induction was sufficient to permanently damage the ability of treated Mel cells and their progeny to undergo erythroid differentiation, without affecting cell viability and proliferation. Conversely, a 5 h pulse of metavanadate at 1 or 10 microg/ml inhibited both differentiation and cell proliferation. The cell cycle-dependent period of mutagenesis was essential for fixation of damage in the cell genome and the progeny of the cells treated with 0.1 or 0.01 microg/ml metavanadate stably inherited an impaired capacity to differentiate. The efficiency of the DNA repair synthesis machinery during the specific period of exposure of Mel cells seemed directly involved in damage fixation. In fact, the mutagenic effects of a 0.1 microg/ml metavanadate pulse was further increased in the presence of 1 mM hydroxyurea, an inhibitor of DNA repair synthesis. In contrast, 5 microg/ml vanillin, an antimutagenic agent that stimulates repair, completely restored the capacity of progeny of cells treated with 0.1 microg/ml metavanadate to complete differentiation. Determination of [(3)H]deoxythymidine in acid-insoluble DNA indicated that incorporation was stimulated by metavanadate alone and was further increased by metavanadate plus vanillin; conversely, incorporation of thymidine was reduced in the presence of hydroxyurea. The capacity of metavanadate to permanently damage Mel cell erythroid differentiation appeared to depend on the cell cycle-related efficiency of the DNA repair systems, activated to correct the induced alteration, rather than on a specific concentration.

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Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals

Grillo

SantaMaria

Kafina

et al. 2017

Science

117

143

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Multiple human diseases ensue from a hereditary or acquired deficiency of iron-transporting protein function that diminishes transmembrane iron flux in distinct sites and directions. Because other iron-transport proteins remain active, labile iron gradients build up across the corresponding protein-deficient membranes. Here we report that a small molecule natural product, hinokitiol, can harness such gradients to restore iron transport into, within, and/or out of cells. The same compound promotes gut iron absorption in DMT1-deficient rats and ferroportin-deficient mice, as well as hemoglobinization in DMT1- and mitoferrin-deficient zebrafish. These findings illuminate a general mechanistic framework for small molecule-mediated site- and direction-selective restoration of iron transport. They also suggest small molecules that partially mimic the function of missing protein transporters of iron, and possibly other ions, may have potential in treating human diseases.

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Two periods of sensitivity to mutagens in induced Mel cells with different outcomes

Cited by 3 publications

References 11 publications

Evidence of Genetic Instability in Tumors and Normal Nearby Tissues

Evidence of Genetic Instability in Tumors and Normal Nearby Tissues

A short low-level exposure to metavanadate during a cell cycle-specific interval of time is sufficient to permanently derange the differentiative properties of Mel cells

Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals

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