PubMed · 14788416
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R CLOUTIER. 1950. [Artificial prostheses for enucleations].. https://pubmed.ncbi.nlm.nih.gov/14788416/
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p53 mutants with a single amino acid substitution are overexpressed in a majority of human cancers containing a p53 mutation. Overexpression of the mutant protein suggests that there is a selection pressure on the cell indicative of an active functional role for mutant p53. Indeed, H1299 cells expressing mutant p53-R175H, p53-R273H or p53-D281G grow at a faster rate compared with a control cell line. Using p53-specific small interfering RNA, we show that the growth rate of mutant p53-expressing cells decreases as mutant p53 level decreases, demonstrating that the increased cellular growth is dependent on p53 expression. Increased growth rate is not observed for H1299 cell clones expressing mutant p53-D281G (L22Q/W23S), which has been shown to be defective in transactivation in transient transcriptional assays. This shows that the increased growth rate imparted by mutant p53 in H1299 cells requires the transactivation function of mutant p53. By performing microarray hybridization analyses, we show that constitutive expression of three common p53 mutants (p53-R175H, p53-R273H, and p53-D281G) in H1299 human lung carcinoma cells evokes regulation of a common set of genes, a significant number of which are involved in cell growth regulation. Predictably, H1299 cells expressing p53-D281G (L22Q/W23S) are defective in up-regulating a number of these genes. The differences in expression profiles induced by individual p53 mutants in the cells may be representative of the p53 mutants and how they can affect gene expression resulting in the observed "gain of function" phenotypes (i.e., increased growth rate, decreased sensitivity to chemotherapeutic agents, and so forth).
BACKGROUND: Hypoxia-tolerant human glioma cells reduce oxygen consumption rate in response to oxygen deficit, a defense mechanism that contributes to survival under moderately hypoxic conditions. In contrast, hypoxia-sensitive cells lack this ability. As it has been previously shown that hypoxia-tolerant (M006x, M006xLo, M059K) and -sensitive (M010b) glioma cells express differences in mitochondrial function, we investigated whether mitochondrial DNA-encoded mutations are associated with differences in the initial response to oxygen deficit. RESULTS: The mitochondrial genome was sequenced and 23 mtDNA alterations were identified, one of which was an unreported mutation (T-C transition in base pair 14634) in the hypoxia-sensitive cell line, M010b, that resulted in a single amino acid change in the gene encoding the ND6 subunit of NADH:ubiquinone oxidoreductase (Complex I). The T14634C mutation did not abrogate ND6 protein expression, however, M010b cells were more resistant to rotenone, an agent used to screen for Complex I mutations, and adriamycin, an agent activated by redox cycling. The specific function of mtDNA-encoded, membrane-embedded Complex I ND subunits is not known at present. Current models suggest that the transmembrane arm of Complex I may serve as a conformationally driven proton channel. As cellular respiration is regulated, in part, by proton flux, we used homology-based modeling and computational molecular biology to predict the 3D structure of the wild type and mutated ND6 proteins. These models predict that the T14634C mutation alters the structure and orientation of the trans-membrane helices of the ND6 protein. CONCLUSION: Complex I ND subunits are mutational hot spots in tumor mtDNA. Genetic changes that alter Complex I structure and function may alter a cell's ability to respond to oxygen deficit and consolidate hypoxia rescue mechanisms, and may contribute to resistance to chemotherapeutic agents that require redox cycling for activation.
A miscellany of new strategies, experimental techniques and theoretical approaches are emerging in the ongoing battle against cancer. Nevertheless, as new, ground-breaking discoveries relating to many and diverse areas of cancer research are made, scientists often have recourse to mathematical modelling in order to elucidate and interpret these experimental findings. Indeed, experimentalists and clinicians alike are becoming increasingly aware of the possibilities afforded by mathematical modelling, recognising that current medical techniques and experimental approaches are often unable to distinguish between various possible mechanisms underlying important aspects of tumour development. This short treatise presents a concise history of the study of solid tumour growth, illustrating the development of mathematical approaches from the early decades of the twentieth century to the present time. Most importantly these mathematical investigations are interwoven with the associated experimental work, showing the crucial relationship between experimental and theoretical approaches, which together have moulded our understanding of tumour growth and contributed to current anti-cancer treatments. Thus, a selection of mathematical publications, including the influential theoretical studies by Burton, Greenspan, Liotta et al., McElwain and co-workers, Adam and Maggelakis, and Byrne and co-workers are juxtaposed with the seminal experimental findings of Gray et al. on oxygenation and radio-sensitivity, Folkman on angiogenesis, Dorie et al. on cell migration and a wide variety of other crucial discoveries. In this way the development of this field of research through the interactions of these different approaches is illuminated, demonstrating the origins of our current understanding of the disease.