排序方式: 共有213条查询结果,搜索用时 156 毫秒
71.
DNA damage initiates a series of p53 pulses. Although much is known about the interactions surrounding p53, little is known about which interactions contribute to p53's dynamical behavior. The simplest explanation is that these pulses are oscillations intrinsic to the p53/Mdm2 negative feedback loop. Here we present evidence that this simple mechanism is insufficient to explain p53 pulses; we show that p53 pulses are externally driven by pulses in the upstream signaling kinases, ATM and Chk2, and that the negative feedback between p53 and ATM, via Wip1, is essential for maintaining the uniform shape of p53 pulses. We propose that p53 pulses result from repeated initiation by ATM, which is reactivated by persistent DNA damage. Our study emphasizes the importance of collecting quantitative dynamic information at high temporal resolution for understanding the regulation of signaling pathways and opens new ways to manipulate p53 pulses to ask questions about their function in response to DNA damage. 相似文献
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Sigal A Milo R Cohen A Geva-Zatorsky N Klein Y Alaluf I Swerdlin N Perzov N Danon T Liron Y Raveh T Carpenter AE Lahav G Alon U 《Nature methods》2006,3(7):525-531
We examined cell cycle-dependent changes in the proteome of human cells by systematically measuring protein dynamics in individual living cells. We used time-lapse microscopy to measure the dynamics of a random subset of 20 nuclear proteins, each tagged with yellow fluorescent protein (YFP) at its endogenous chromosomal location. We synchronized the cells in silico by aligning protein dynamics in each cell between consecutive divisions. We observed widespread (40%) cell-cycle dependence of nuclear protein levels and detected previously unknown cell cycle-dependent localization changes. This approach to dynamic proteomics can aid in discovery and accurate quantification of the extensive regulation of protein concentration and localization in individual living cells. 相似文献
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Martens N Uzan G Wery M Hooghe R Hooghe-Peters EL Gertler A 《The Journal of biological chemistry》2005,280(14):13817-13823
We report here the role of one of the less studied members of the family of suppressors of cytokine signaling (SOCS), namely SOCS-7, in cytokine signaling. We demonstrate that SOCS-7 inhibits prolactin (PRL), growth hormone (GH), or leptin (LEP) signaling mediated through STAT3 and STAT5 in a dose-dependent manner. SOCS-7 also attenuated STAT3 and STAT5 signaling induced by overexpression of JH1, the catalytic subdomain of JAK2. Since SOCS-7 interacted with phosphorylated STAT3 or STAT5, we assumed that SOCS-7 acts at the level of STAT proteins. Indeed, we showed that SOCS-7 inhibits PRL- and leptin-induced STAT5 and STAT3 phosphorylation and prevented the nuclear translocation of activated STAT3. Taken together, our results indicate that SOCS-7 is a physiological dysregulator of PRL, leptin, and probably also GH signaling and that its mode of action is a novel variation of SOCS protein inhibition of cytokine-inducible STAT-mediated signal transduction. 相似文献
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Alter G Malenfant JM Delabre RM Burgett NC Yu XG Lichterfeld M Zaunders J Altfeld M 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(8):5305-5311
NK cells are a subset of granular lymphocytes that are critical in the innate immune response to infection. These cells are capable of killing infected cells and secreting integral cytokines and chemokines. The role that this subset of cytolytic cells plays in HIV infection is not well understood. In this study, we dissected the function of NK cells in viremic and aviremic HIV-1-infected subjects, as well as HIV-1-negative control individuals. Despite reduced NK cell numbers in subjects with ongoing viral replication, these cells were significantly more active in secreting both IFN-gamma and TNF-alpha than NK cells from aviremic subjects or HIV-1-negative controls. In addition, NK cells in subjects with detectable viral loads expressed significantly higher levels of CD107a, a marker of lysosomal granule exocytosis. The expression of CD107a correlated with NK cell-mediated cytokine secretion and cytolytic activity as well as with the level of viral replication, suggesting that CD107a represents a good marker for the functional activity of NK cells. Finally, killer Ig-related receptor+ NK cells were stable or elevated in viremic subjects, while the numbers of CD3-/CD56+/CD94+ and CD3-/CD56+/CD161+ NK cells were reduced. Taken together, these data demonstrate that viremic HIV-1 infection is associated with a reduction in NK cell numbers and a perturbation of NK cell subsets, but increased overall NK cell activity. 相似文献
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High‐resolution definition of humoral immune response correlates of effective immunity against HIV 下载免费PDF全文
Galit Alter Karen G Dowell Eric P Brown Todd J Suscovich Anastassia Mikhailova Alison E Mahan Bruce D Walker Falk Nimmerjahn Chris Bailey‐Kellogg Margaret E Ackerman 《Molecular systems biology》2018,14(3)
Defining correlates of immunity by comprehensively interrogating the extensive biological diversity in naturally or experimentally protected subjects may provide insights critical for guiding the development of effective vaccines and antibody‐based therapies. We report advances in a humoral immunoprofiling approach and its application to elucidate hallmarks of effective HIV‐1 viral control. Systematic serological analysis for a cohort of HIV‐infected subjects with varying viral control was conducted using both a high‐resolution, high‐throughput biophysical antibody profiling approach, providing unbiased dissection of the humoral response, along with functional antibody assays, characterizing antibody‐directed effector functions such as complement fixation and phagocytosis that are central to protective immunity. Profiles of subjects with varying viral control were computationally analyzed and modeled in order to deconvolute relationships among IgG Fab properties, Fc characteristics, and effector functions and to identify humoral correlates of potent antiviral antibody‐directed effector activity and effective viral suppression. The resulting models reveal multifaceted and coordinated contributions of polyclonal antibodies to diverse antiviral responses, and suggest key biophysical features predictive of viral control. 相似文献
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Frederick W. Holtsberg Sergey Shulenin Hong Vu Katie A. Howell Sonal J. Patel Bronwyn Gunn Marcus Karim Jonathan R. Lai Julia C. Frei Elisabeth K. Nyakatura Larry Zeitlin Robin Douglas Marnie L. Fusco Jeffrey W. Froude Erica Ollmann Saphire Andrew S. Herbert Ariel S. Wirchnianski Calli M. Lear-Rooney Galit Alter John M. Dye Pamela J. Glass Kelly L. Warfield M. Javad Aman 《Journal of virology》2016,90(1):266-278
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Alina Kurolap Anja Armbruster Tova Hershkovitz Katharina Hauf Adi Mory Tamar Paperna Ewald Hannappel Galit Tal Yusif Nijem Ella Sella Muhammad Mahajnah Anat Ilivitzki Dov Hershkovitz Nina Ekhilevitch Hanna Mandel Volker Eulenburg Hagit N. Baris 《American journal of human genetics》2016,99(5):1172-1180