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1.
Ivana Tonic Wan-Ni Yu Youngku Park Chia-Chen Chen Nissim Hay 《The Journal of biological chemistry》2010,285(31):23790-23798
Akt is perhaps the most frequently activated oncoprotein in human cancers. Overriding cell cycle checkpoint in combination with the inhibition of apoptosis are two principal requirements for predisposition to cancer. Here we show that the activation of Akt is sufficient to promote these two principal processes, by inhibiting Chk1 activation with concomitant inhibition of apoptosis. These activities of Akt cannot be recapitulated by the knockdown of Chk1 alone or by overexpression of Bcl2. Rather the combination of Chk1 knockdown and Bcl2 overexpression is required to recapitulate Akt activities. Akt was shown to directly phosphorylate Chk1. However, we found that Chk1 mutants in the Akt phosphorylation sites behave like wild-type Chk1 in mediating G2 arrest, suggesting that the phosphorylation of Chk1 by Akt is either dispensable for Chk1 activity or insufficient by itself to exert an effect on Chk1 activity. Here we report a new mechanism by which Akt affects G2 cell cycle arrest. We show that Akt inhibits BRCA1 function that induces G2 cell cycle arrest. Akt prevents the translocation of BRCA1 to DNA damage foci and, thereby, inhibiting the activation of Chk1 following DNA damage. 相似文献
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4.
《Current biology : CB》2022,32(1):74-85.e4
Download : Download video (38MB) 相似文献
5.
Bo Lin Dipika Gupta Christopher D. Heinen 《The Journal of biological chemistry》2014,289(35):24314-24324
Human pluripotent stem cells (PSCs) are presumed to have robust DNA repair pathways to ensure genome stability. PSCs likely need to protect against mutations that would otherwise be propagated throughout all tissues of the developing embryo. How these cells respond to genotoxic stress has only recently begun to be investigated. Although PSCs appear to respond to certain forms of damage more efficiently than somatic cells, some DNA damage response pathways such as the replication stress response may be lacking. Not all DNA repair pathways, including the DNA mismatch repair (MMR) pathway, have been well characterized in PSCs to date. MMR maintains genomic stability by repairing DNA polymerase errors. MMR is also involved in the induction of cell cycle arrest and apoptosis in response to certain exogenous DNA-damaging agents. Here, we examined MMR function in PSCs. We have demonstrated that PSCs contain a robust MMR pathway and are highly sensitive to DNA alkylation damage in an MMR-dependent manner. Interestingly, the nature of this alkylation response differs from that previously reported in somatic cell types. In somatic cells, a permanent G2/M cell cycle arrest is induced in the second cell cycle after DNA damage. The PSCs, however, directly undergo apoptosis in the first cell cycle. This response reveals that PSCs rely on apoptotic cell death as an important defense to avoid mutation accumulation. Our results also suggest an alternative molecular mechanism by which the MMR pathway can induce a response to DNA damage that may have implications for tumorigenesis. 相似文献
6.
Alvaro García-Tejedor A. Raul Castaño Federico Morán Francisco Montero 《Journal of molecular evolution》1987,26(4):294-300
Summary The most relevant properties of hypercycles were previously studied mainly from a theoretical point of view. We have developed a Monte Carlo method simulating hypercyclic organization to obtain information about the dynamics of this prebiotic organization. Nucleation, growth, and selective properties have been tested and the results obtained are in good agreement with those of the theoretical predictions. The influence of hypercyclic organization of the error threshold has also been studied. As a consequence of the emergence of a hypercycle, the value of this threshold decreases. The amount of this decrease depends on the population size. Moreover, for some interval of quality factor values, either the hypercycle organization or an error catastrophe can be produced, depending on the initial conditions. The influence of these phenomena on both the dynamic behavior and evolutionary advantages of the hypercycle, as well as their decisive roles on genome size, are discussed.Presented at the FEBS Symposium on Genome Organization and Evolution, held in Crete, Greece, September 1–5, 1986 相似文献
7.
Experiments were conducted for 3 years at four locations and 1 year with six soil types at a common location in North Carolina to determine damage and control-cost functions for Heterodera glycines races 1 and 2 on soybean. In the experiments on native loamy sand and sandy soils, tolerance limits for initial population densities were 0 or very low, whereas in a muck, the tolerance limit was 315 eggs/500 cm³ soil. The aggressive race 2 was more damaging than race 1 in Lakeland sand and Norfolk loamy sand. The crop response was not different between races in the Appling sandy clay loam and Belhaven muck. Soybean yield responses to H. glycines were linear in six soil types in microplots at a common site. The amount of damage varied among these soil types, with lowest yields in the muck because of severe drought stress in this soil. An exponential function adequately described soybean yield response relative to nematode control with increasing rates of aldicarb in Norfolk loamy sand. Treatment with aldicarb in the Lakeland sand decreased the effective egg population of H. glycines but had only a minor effect in the muck. 相似文献
8.
Summary This paper describes the ovarian pathologies observed when 108 different heteroallelic combinations were made involving 17 independent mutations at the ovarian tumor (otu) locus. Most of the mutant phenotypes can be explained as graded responses by individual germ cells to different levels of functionally active otu gene product (OGP) synthesized by the mutant cells themselves. The lowest and highest levels of OGP appear to be produced by otu
10 and otu
14, respectively. In most heteroallelic ovaries the alleles have additive effects, and hybrid germ cells reach a developmental stage more advanced than the weaker homozygote but less advanced than the stronger homozygote. However, examples of both positive and negative complementation also have been found, and these suggest that the products encoded by different mutant alleles can combine to form dimers or multimers which may be superior or inferior to the homodimers. In flies homozygous for otu
11 most ovarioles contain tumors, but some germ cells are able to develop further than those in otu
14 homozygotes. This suggests that, while otu
11 produces intermediate levels of OGP, it also produces a second product (which otu
14 cannot make) that is utilized at the period in oogenesis when development in cells homozygous for otu
14 is blocked. When otu
11 is combined with any one of eight specific alleles, it allows oocyte/nurse cell syncytia to differentiate that can complete development and undergo embryogenesis, if fertilized. The endopolyploid nurse cells of these hybrids have giant polytene chromosomes, and the presence of GPCs in functionally active, germ-line derived cells provides an interesting new system for experimental study. Analysis of the characteristic ovarian pathologies produced by flies of different genotypes leads to the conclusion that the products of the otu
+ gene are utilized during at least six different periods in Drosophila oogenesis. 相似文献
9.
The ethanol-oxidizing, proton-reducing Pelobacter acetylenicus was grown in chemostat cocultures with either Acetobacterium woodii, Methanobacterium bryantii, or Desulfovibrio desulfuricans. Stable steady state conditions with tightly coupled growth were reached at various dilution rates between 0.02 and 0.14 h-1. Both ethanol and H2 steady state concentrations increased with growth rate and were lower in cocultures with the sulfate reducer < methanogen < homoacetogen. Due to the higher affinity for H2, D. desulfuricans outcompeted M. bryantii, and this one A. woodii when inoculated in cocultures with P. acetylenicus. Cocultures with A. woodii had lower H2 steady state concentrations when bicarbonate reduction was replaced by the energetically more favourable caffeate reduction. Similarly, cocultures with D. desulfuricans had lower H2 concentrations with nitrate than with sulfate as electron acceptor. The Gibbs free energy (G) available to the H2-producing P. acetylenicus was independent of growth rate and the H2-utilizing partner, whereas the G available to the latter increased with growth rate and the energy yielding potential of the H2 oxidation reaction. The critical Gibbs free energy (Gc), i.e. the minimum energy required for H2 production and H2 oxidation, was-5.5 to-8.0 kJ mol-1 H2 for P. acetylenicus,-5.1 to-6.3 kJ mol-1 H2 for A. woodii,-7.5 to-9.1 kJ mol-1 H2 for M. bryantii, and-10.3 to-12.3 kJ mol-1 H2 for D. desulfuricans. Obviously, the potentially available energy was used more efficiently by homoacetogens > methanogens > sulfate reducers. 相似文献
10.
Hiroshi Yao Hiroaki Ooboshi Seizo Sadoshima Kentaro Takano Setsuro Ibayashi Masatoshi Fujishima 《Neurochemical research》1990,15(5):547-549
To determine the level of cerebral blood flow reduction which causes striatal dopamine release, extracellular dopamine and cerebral blood flow was simultaneously determined using in vivo brain dialysis and a hydrogen clearance method, respectively, in the striatum of spontaneously hypertensive rats, before and during experimental cerebral ischemia. The ischemic flow threshold for neurotransmitter dopamine release was found to be 20% of the resting value or 8–10 ml/100g/min of cerebral blood flow, being similar to those for energy and membrane failures. 相似文献