Cancer stem cells.
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Cell Transformation, Neoplastic↗
Biomedical subjects
Didier Wion
Publications and source records attributed to Didier Wion.
Glioma, melatonin, and radiotherapy.
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Animals↗
Undetectable levels of N6-methyl adenine in mouse DNA: Cloning and analysis of PRED28, a gene coding for a putative mammalian DNA adenine methyltransferase.
Three methylated bases, 5-methylcytosine, N4-methylcytosine and N6-methyladenine (m6A), can be found in DNA. However, to date, only 5-methylcytosine has been detected in mammalian genomes. To reinvestigate the presence of m6A in mammalian DNA, we used a highly sensitive method capable of detecting one N6-methyldeoxyadenosine per million nucleosides. Our results suggest that the total mouse genome contains, if any, less than 10(3) m6A. Experiments were next performed on PRED28, a putative mammalian N6-DNA methyltransferase. The murine PRED28 encodes two alternatively spliced RNA. However, although recombinant PRED28 proteins are found in the nucleus, no evidence for an adenine-methyltransferase activity was detected.
Adenine↗
N6-methyladenine: the other methylated base of DNA.
Contrary to mammalian DNA, which is thought to contain only 5-methylcytosine (m5C), bacterial DNA contains two additional methylated bases, namely N6-methyladenine (m6A), and N4-methylcytosine (m4C). However, if the main function of m5C and m4C in bacteria is protection against restriction enzymes, the roles of m6A are multiple and include, for example, the regulation of virulence and the control of many bacterial DNA functions such as the replication, repair, expression and transposition of DNA. Interestingly, even if adenine methylation is usually considered a bacterial DNA feature, the presence of m6A has been found in protist and plant DNAs. Furthermore, indirect evidence suggests the presence of m6A in mammal DNA, raising the possibility that this base has remained undetected due to the low sensitivity of the analytical methods used. This highlights the importance of considering m6A as the sixth element of DNA.
Adenine↗
N6-methyl-adenine: an epigenetic signal for DNA-protein interactions.
N(6)-methyl-adenine is found in the genomes of bacteria, archaea, protists and fungi. Most bacterial DNA adenine methyltransferases are part of restriction-modification systems. Certain groups of Proteobacteria also harbour solitary DNA adenine methyltransferases that provide signals for DNA-protein interactions. In gamma-proteobacteria, Dam methylation regulates chromosome replication, nucleoid segregation, DNA repair, transposition of insertion elements and transcription of specific genes. In Salmonella, Haemophilus, Yersinia and Vibrio species and in pathogenic Escherichia coli, Dam methylation is required for virulence. In alpha-proteobacteria, CcrM methylation regulates the cell cycle in Caulobacter, Rhizobium and Agrobacterium, and has a role in Brucella abortus infection.
Adenine↗
Should we control the pineal status of patients following brain radiotherapy?
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Brain Neoplasms↗
RNA mutagenesis and sporadic prion diseases.
The extremely low incidence of sporadic prion diseases suggests that they may arise as a rare stochastic event in otherwise healthy animals or humans. Current hypotheses for sporadic prion disease include horizontal transmission, spontaneous conversion of PrpC into PrpSc, and somatic mutation of the Prp gene. Here, we suggest RNA mutation as a possible initial event in the etiology of sporadic prion disease. The proposed model is based on (i) the fact that in Prp-expressing cells, mutations are statistically more likely to occur in the Prp mRNA population than in the corresponding two copies of the Prp gene, and (ii) the absence of RNA repair mechanisms analogous to those found for DNA mismatch correction resulting in a relatively higher rate of RNA mutations. Here, we suggest that translation of mutated Prp mRNA could lead to the synthesis of transient Prp(Sc) which results in the conversion of PrpC into PrpSc and the propagation of a disease-associated isoform. This model points to RNA mutation as a possible mechanism for the generation of sporadic prion diseases and other pathological disorders in which infectious proteins other than PrpSc might be implicated.
Animals↗
N(6)-Methyldeoxyadenosine, a nucleoside commonly found in prokaryotes, induces C2C12 myogenic differentiation.
N(6)-methyl-2(')-deoxyadenosine (MedAdo) is a nucleoside naturally found in prokaryotic DNA. Interestingly, the N(6)-methylation of adenine in DNA seems to have been counter-selected during the course of evolution since MedAdo has not been detected in mammalian DNA until now. We show here that treatment with MedAdo induces myogenesis in C2C12 myoblasts. The presence of MedAdo in C2C12 DNA was investigated using a method based on HPLC coupled to electrospray ionization tandem mass spectrometry which is several thousand fold more sensitive than assays used previously. By this procedure, MedAdo is detected in the DNA from MedAdo-treated cells but remains undetectable in the DNA from control cells. Furthermore, MedAdo regulates the expression of p21, myogenin, mTOR, and MHC. Interestingly, in the pluripotent C2C12 cell line, MedAdo drives the differentiation towards myogenesis only. Thus, the biological effect of MedAdo is suppressed in the presence of BMP-2 which transdifferentiates C2C12 from myogenic into osteogenic lineage cells. Taken together these results point to MedAdo as a novel inducer of myogenesis and further extends the differentiation potentialities of this methylated nucleoside. Furthermore, these data raise the intriguing possibility that the biological effects of MedAdo on cell differentiation may have led to its counter-selection in eukaryotes.
Adenine↗
Development of gliomas: potential role of asymmetrical cell division of neural stem cells.
Asymmetrical cell division is a mechanism that gives rise to two daughter cells with different proliferative and differentiative fates. It occurs mainly during development and in adult stem cells. Accumulating evidence suggests that tumour cells arise from the transformation of normal stem cells. Here, we propose that the asymmetrical mitosis potential of stem cells is associated with the generation of migrating tumour progenitors. Application of this speculative model to glioma proposes that the sites where tumour-initiating stem cells reside are indolent and distinct from the tumour mass, and implies that the tumour mass is continuously replenished with new migrating tumour cells from these clinically silent regions. This hypothesis offers explanations for our inability to cure glioblastoma and points to asymmetrical division as a new potential therapeutic target.
Brain Neoplasms↗
Induction of neurite outgrowth in PC12 cells by the bacterial nucleoside N6-methyldeoxyadenosine is mediated through adenosine A2a receptors and via cAMP and MAPK signaling pathways.
We have previously shown that N(6)-methyldeoxyadenosine (MDA) is an inducer of differentiation in several tumor cells. Here we show that in addition to its ability to induce neurite-outgrowth in PC12 cells, MDA also significantly enhances the nerve-growth factor-mediated neurite outgrowth of these cells. Thus, MDA acts synergistically with NGF to repress cdc2 and cdk2 synthesis and to enhance tyrosine hydroxylase synthesis. To further elucidate the mechanisms of action of MDA, we investigated the effect of this drug on various signaling pathways. The neuritogenesis observed in PC12 following MDA treatment is mediated through activation of adenylyl cyclase in a PKA independent process and through the recruitment of the p44/p42 MAPK pathway. Furthermore, the adenosine A(2a) receptor antagonist ZM 241385 prevents the MDA-induced neuritogenesis, suggesting that MDA mediates its effect via this adenylyl cyclase-coupled A(2a) receptor. Collectively, these findings suggest that, in PC12 cells, the MDA-induced neuritogenesis requires the recruitment of adenosine A(2a) receptor, the stimulation of adenylate cyclase, and the activation of the p44/42MAP kinase cascade.
Adenosine↗
What is, mutatis mutandis, the sequence of plasmid DNAs used in gene therapy?
Mutation is a fundamental biological process occurring in each living organism. Plasmid DNA which is used in gene therapy protocols or DNA vaccination passes through two different living cells which are, respectively, the producing cell (bacterial) and the target cell (eukaryotic). Hence, modifications in the nucleotide sequence of plasmids are likely to occur both in bacteria during the amplification step of plasmid DNA and in eukaryotic cells following gene transfer. In addition to these biological modifications resulting from the physical passage of the plasmid into two different living organisms, an additional source of sequence alteration resides in our mode of representation of the nucleotide sequence of plasmid DNA which uses a four letters code, whereas, bacterial DNA is made of six different nucleosides. Indeed, the therapeutic DNA paradigm seems to have neglected the qualitative importance of these DNA sequence alterations. In this review we discuss the importance and the role of these DNA sequence modifications in the context of non-viral gene therapy approaches.
DNA↗
New clues about vitamin D functions in the nervous system.
Accumulating data have provided evidence that 1 alpha,25 dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is involved in brain function. Thus, the nuclear receptor for 1,25-(OH)(2)D(3) has been localized in neurons and glial cells. Genes encoding the enzymes involved in the metabolism of this hormone are also expressed in brain cells. The reported biological effects of 1,25-(OH)(2)D(3) in the nervous system include the biosynthesis of neurotrophic factors and at least one enzyme involved in neurotransmitter synthesis. 1,25-(OH)(2)D(3) can also inhibit the synthesis of inducible nitric oxide synthase and increase glutathione levels, suggesting a role for the hormone in brain detoxification pathways. Neuroprotective and immunomodulatory effects of this hormone have been described in several experimental models, indicating the potential value of 1,25-(OH)(2)D(3) pharmacological analogs in neurodegenerative and neuroimmune diseases. In addition, 1,25-(OH)(2)D(3) induces glioma cell death, making the hormone of potential interest in the management of brain tumors. These results reveal previously unsuspected roles for 1,25-(OH)(2)D(3) in brain function and suggest possible areas of future research.
Animals↗