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21.
Jun-Sub Im Soon-Young Park Won-Ho Cho Sung-Ho Bae Jerard Hurwitz Joon-Kyu Lee 《Cell cycle (Georgetown, Tex.)》2015,14(7):1001-1009
Though RecQL4 was shown to be essential for the initiation of DNA replication in mammalian cells, its role in initiation is poorly understood. Here, we show that RecQL4 is required for the origin binding of Mcm10 and Ctf4, and their physical interactions and association with replication origins are controlled by the concerted action of both CDK and DDK activities. Although RecQL4-dependent binding of Mcm10 and Ctf4 to chromatin can occur in the absence of pre-replicative complex, their association with replication origins requires the presence of the pre-replicative complex and CDK and DDK activities. Their association with replication origins and physical interactions are also targets of the DNA damage checkpoint pathways which prevent initiation of DNA replication at replication origins. Taken together, the RecQL4-dependent association of Mcm10 and Ctf4 with replication origins appears to be the first important step controlled by S phase promoting kinases and checkpoint pathways for the initiation of DNA replication in human cells. 相似文献
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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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The relation between hypertension and cognition in elders remains unclear, and studies on the effect of antihypertensive drugs on cognition have demonstrated conflicting results. This study was performed to evaluate if the association between hypertension and cognition in elders differed depending on serum concentrations of organochlorine (OC) pesticides, common neurotoxic chemicals. Participants were 644 elders aged 60–85 years who participated in the National Health and Nutrition Examination Survey 1999–2002 and were able to complete a cognitive test. We selected 6 OC pesticides that were commonly detected in the elderly. Cognition was assessed by the Digit Symbol Substitution Test (DSST), a relevant tool for evaluating hypertension-related cognitive function, and low cognition was defined by the DSST score < 25th percentile. When OC pesticides were not considered in the analyses, elders with hypertension had about 1.7 times higher risk of low cognition than those without hypertension. However, in analyses stratified by serum concentrations of OC pesticides, the associations between hypertension and low cognition were stronger the higher the serum concentrations of p,p’-DDT, p,p’-DDE, β-hexachlorocyclohexane, and trans-nonachlor increased. Among elders in the 3rd tertile of these pesticides, adjusted odds ratios were from 2.5 to 3.5. In contrast, hypertension was not clearly associated with the risk of low cognition in elders in the 1st tertile of these pesticides. Similar patterns were observed for the continuous DSST score dependent variable. The difference in the association between hypertension and DSST scores according to the levels of OC pesticides suggest a key role of OC pesticides in the development of hypertension-related cognitive impairment and may help to identify hypertensive elders who are at a high risk of cognitive impairment. 相似文献
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T Asai C S Lee A Chandler W J O'Sullivan 《Comparative biochemistry and physiology. B, Comparative biochemistry》1990,95(1):159-163
1. Uracil phosphoribosyltransferase (UPRTase) was purified 370-fold from the protozoan parasite, Crithidia luciliae. 2. The enzyme was a dimer of mol. wt 80 000 and was highly specific for uracil. 3. GTP, which is an activator of UPRTase from E. coli had a slight inhibitory effect on the parasite enzyme. 4. The C. luciliae UPRTase demonstrated a broad specificity for activating divalent metal ions. 相似文献
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So Jeong Park Doo Ri Park Deepak Bhattarai Kyeong Lee Jaesang Kim Yun Soo Bae Soo Young Lee 《Molecules and cells》2014,37(8):628-635
2-(Trimethylammonium) ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate [(R)-TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient megakaryopoiesis. Here, we show that (R)-TEMOSPho blocks osteoclast maturation from progenitor cells of hematopoietic origin, as well as blocking the resorptive function of mature osteoclasts. The inhibitory effect of (R)-TEMOSPho on osteoclasts was due to a disruption of the actin cytoskeleton, resulting from impaired downstream signaling of c-Fms, a receptor for macrophage-colony stimulating factor linked to c-Cbl, phosphoinositol-3-kinase (PI3K), Vav3, and Rac1. In addition, (R)-TEMOSPho blocked inflammation-induced bone destruction by reducing the numbers of osteoclasts produced in mice. Thus, (R)-TEMOSPho may represent a promising new class of antiresorptive drugs for the treatment of bone loss associated with increased osteoclast maturation and activity. 相似文献
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Mitochondrial DNA (mtDNA) copy number in peripheral blood has been suggested as risk modifier in various types of cancer. However, its influence on melanoma risk is unclear. We evaluated the association between mtDNA copy number in peripheral blood and melanoma risk in 500 melanoma cases and 500 healthy controls from an ongoing melanoma study. The mtDNA copy number was measured using real-time polymerase chain reaction. Overall, mean mtDNA copy number was significantly higher in cases than in controls (1.15 vs 0.99, P<0.001). Increased mtDNA copy number was associated with a 1.45-fold increased risk of melanoma (95% confidence interval: 1.12-1.97). Significant joint effects between mtDNA copy number and variables related to pigmentation and history of sunlight exposure were observed. This study supports an association between increased mtDNA copy number and melanoma risk that is independent on the known melanoma risk factors (pigmentation and history of sunlight exposure). 相似文献
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