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Xinzhu Deng David Michaelson Jason Tchieu Jin Cheng Diana Rothenstein Regina Feldman Sang-gyu Lee John Fuller Adriana Haimovitz-Friedman Lorenz Studer Simon Powell Zvi Fuks E. Jane Albert Hubbard Richard Kolesnick 《PloS one》2015,10(6)
Mammalian NOTCH1-4 receptors are all associated with human malignancy, although exact roles remain enigmatic. Here we employ glp-1(ar202), a temperature-sensitive gain-of-function C. elegans NOTCH mutant, to delineate NOTCH-driven tumor responses to radiotherapy. At ≤20°C, glp-1(ar202) is wild-type, whereas at 25°C it forms a germline stem cell⁄progenitor cell tumor reminiscent of human cancer. We identify a NOTCH tumor phenotype in which all tumor cells traffic rapidly to G2⁄M post-irradiation, attempt to repair DNA strand breaks exclusively via homology-driven repair, and when this fails die by mitotic death. Homology-driven repair inactivation is dramatically radiosensitizing. We show that these concepts translate directly to human cancer models. 相似文献
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Biomechanical and morphometric comparisons among coleoptilesfrom wheat seedlings differing in Rht gene-dosage (Rht = 0,2, 4 doses) are presented in an effort to evaluate the influenceof Rht on the mechanics of soil penetration by this organ. Rhtis known to reduce seedling establishment compared to the wildtype. Data from 37-day-old seedlings indicate that Rhtreduces tissue elastic modulus E, increases the second momentof area I, and decreases the slenderness ratio (l/r) of coleoptiles.Rht-relatedchanges in E and I are such that the flexural stiffness of coleoptilesfrom Rht plants does not differ significantly from the wildtype-hence the growing coleoptiles of all three genotypes haveequivalent biomechanical capacity to penetrate the soil. Rhtreduction of coleoptile slenderness ratios confers a capacityto safely sustain higher axial compressive loads compared tocoleoptiles with equivalent flexural stiffness but higher ratios.However, wild type seedlings produce longer coleoptiles andlonger subcrown internodes than Rht seedlings. Longer coleoptilesdeliver the crown node closer to the top of the soil beforethe crown node extends beyond the lateral confinement of thecoleoptile. This reduces the potential for buckling of the subcrowninternode and leaves due to the compressive loading of soil.Rht affects a variety of mechanical features whose influenceis dependent upon the stage of seedling growth and the degreeof soil compaction. However, at equivalent depths of burialwhich exceed the maximum length of coleoptiles and moderatesoil compaction, Rht is biomechanically disadvantageous to seedlingestablishment. Wheat, germination, biomechanics, Rht-gene 相似文献
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S E Unkles I S Heck M V Appleyard J R Kinghorn 《The Journal of biological chemistry》1999,274(27):19286-19293
We describe the primary structure of eukaryotic molybdopterin synthase small and large subunits and compare the sequences of the lower eukaryote, Aspergillus nidulans, and a higher eukaryote, Homo sapiens. Mutants in the A. nidulans cnxG (encoding small subunit) and cnxH (large subunit) genes have been analyzed at the biochemical and molecular level. Chlorate-sensitive mutants, all the result of amino acid substitutions, were shown to produce low levels of molybdopterin, and growth tests suggest that they have low levels of molybdoenzymes. In contrast, chlorate-resistant cnx strains have undetectable levels of molybdopterin, lack the ability to utilize nitrate or hypoxanthine as sole nitrogen sources, and are probably null mutations. Thus on the basis of chlorate toxicity, it is possible to distinguish between amino acid substitutions that permit a low level of molybdopterin production and those mutations that completely abolish molybdopterin synthesis, most likely reflecting molybdopterin synthase activity per se. Residues have been identified that are essential for function including the C-terminal Gly of the small subunit (CnxG), which is thought to be crucial for the sulfur transfer process during the formation of molybdopterin. Two independent alterations at residue Gly-148 in the large subunit, CnxH, result in temperature sensitivity suggesting that this residue resides in a region important for correct folding of the fungal protein. Many years ago it was proposed, from data showing that temperature-sensitive cnxH mutants had thermolabile nitrate reductase, that CnxH is an integral part of the molybdoenzyme nitrate reductase (MacDonald, D. W., and Cove, D. J. (1974) Eur. J. Biochem. 47, 107-110). Studies of temperature-sensitive cnxH mutants isolated in the course of this study do not support this hypothesis. Homologues of both molybdopterin synthase subunits are evident in diverse eukaryotic sources such as worm, rat, mouse, rice, and fruit fly as well as humans as discussed in this article. In contrast, molybdopterin synthase homologues are absent in the yeast Saccharomyces cerevisiae. Precursor Z and molybdopterin are undetectable in this organism nor do there appear to be homologues of molybdoenzymes. 相似文献
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Dynorphin-Related Opioid Peptides in the Neurointermediate Pituitary of Rats Are Not α-N-Acetylated 总被引:1,自引:1,他引:0
Immunoreactive dynorphin in the neurointermediate pituitary of rats was found to consist of four different molecular weight forms. The three larger molecular weight forms, with apparent molecular weights of 4800, 3200, and 1700, constituted more than 80% of the total dynorphin immunoreactivity, and each liberated leucine-enkephalin but not alpha-N-acetyl-leucine-enkephalin upon enzymatic treatment with trypsin followed by carboxypeptidase B. Only a minor portion of the smallest dynorphin-related molecular weight form, dynorphin-(1-8), released alpha-N-acetyl-leucine-enkephalin upon enzymatic cleavage. This suggests that the vast majority of dynorphin-related peptides in the rat neurointermediate pituitary is not alpha-N-acetylated. The exceptionally high opiate-like activity of the molecular weight 1700 dynorphin suggests that this dynorphin-related opioid peptide may constitute the major part of opioid activity in the neurointermediate pituitary of rats. 相似文献