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Mutant
About: Mutant is a research topic. Over the lifetime, 74520 publications have been published within this topic receiving 3477079 citations.
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TL;DR: Mechanisms by which Mutant p53 exerts its cellular effects are reviewed, with a particular focus on the burgeoning mutant p53 transcriptome, and the biological and clinical consequences of mutant p 53 gain of function are discussed.
Abstract: There is now strong evidence that mutation not only abrogates p53 tumor-suppressive functions, but in some instances can also endow mutant proteins with novel activities. Such neomorphic p53 proteins are capable of dramatically altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 may confer unique activities and thereby offer insight into the mutagenic events that drive tumor progression. Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function.
1,033 citations
TL;DR: The primary structure of the encoded protein was deduced from sequence analysis of a corresponding cDNA clone, and the size of this predicted protein was reduced by 40% due to the presence of a point mutation that introduced a premature stop codon.
Abstract: Arabidopsis abi3 mutants are altered in various aspects of seed development and germination that reflect a decreased responsiveness to the hormone abscisic acid. The ABI3 gene has been isolated by positional cloning. A detailed restriction fragment length polymorphism (RFLP) map of the abi3 region was constructed. An RFLP marker closely linked to the abi3 locus was identified, and by analyzing an overlapping set of cosmid clones containing this marker, the abi3 locus was localized within a 35-kb region. An 11-kb subfragment was then shown to complement the mutant phenotype in transgenic plants, thereby further delimiting the position of the locus. A candidate ABI3 gene was identified within this fragment as being expressed in developing fruits. The primary structure of the encoded protein was deduced from sequence analysis of a corresponding cDNA clone. In the most severe abi3-4 allele, the size of this predicted protein was reduced by 40% due to the presence of a point mutation that introduced a premature stop codon. The predicted ABI3 protein displays discrete regions of high similarity to the maize viviparous-1 protein.
1,033 citations
TL;DR: It is shown that the endosperms of maize seeds homozygous for the opaque-2 mutant gene have a higher lysine content than normal kernels and the synthesis of proteins with a greater content of basic amino acids in the acid-soluble fraction of the mutant endosperm.
Abstract: Preliminary tests have shown that the endosperms of maize seeds homozygous for the opaque-2 mutant gene have a higher lysine content than normal kernels. As a critical test, a backcross progeny was divided into opaque-2 and normal kernels, the endosperms separated, and the amino acids determined. The opaque-2 endosperms had a different amino acid pattern and 69 percent more lysine than the normal seeds. The major reason for these changes is the synthesis of proteins with a greater content of basic amino acids in the acid-soluble fraction of the mutant endosperm. This is accompanied by a reduction in the ratio of zein to glutelin.
1,031 citations
TL;DR: It is concluded that overexpression of p53 is synonymous with mutation, but some mutations would not be detected by a simple immunohistochemical analysis.
Abstract: Immunohistological staining of primary colorectal carcinomas with antibodies specific to p53 demonstrated gross overexpression of the protein in approximately 50% of the malignant tumors examined. Benign adenomas were all negative for p53 overexpression. To determine the molecular basis for this overexpression we examined p53 protein expression in 10 colorectal cancer cell lines. Six of the cell lines expressed high levels of p53 in ELISA, cell-staining, and immunoprecipitation studies. Direct sequencing and chemical-mismatch-cleavage analysis of p53 cDNA by using the polymerase chain reaction in these cell lines showed that all cell lines that expressed high levels of p53 were synthesizing mRNAs that encoded mutant p53 proteins. In two of those four cell lines where p53 expression was lower, point mutations were still detected. Thus, we conclude that overexpression of p53 is synonymous with mutation, but some mutations would not be detected by a simple immunohistochemical analysis. Mutation of the p53 gene is one of the commonest genetic changes in the development of human colorectal cancer.
1,024 citations
TL;DR: The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy, and isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers, is examined.
Abstract: The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant--but not IDH1-wild-type--glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.
1,018 citations