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91.
Jun Li Yedan Zhu Miaohong Xie Qian Zhang Wenting Du 《Chemical biology & drug design》2019,94(4):1760-1767
Four compounds T1 , T2 , T3 , and T4 were designed and synthesized as Vorinostat and Belinostat derivatives being the target water‐soluble prodrugs. The water solubility of Vorinostat derivatives, T1 and T2 , exhibited 400‐ to 600‐fold higher than that of Vorinostat, and Belinostat derivatives, T3 and T4 , showed 600‐ to 750‐fold higher than that of Belinostat. Four compounds were evaluated for their inhibitory activities against tumor cell lines HT‐29 and Hut‐78 in the absence or presence of β‐D‐glucuronidase. The inhibitory effects of T1 and T2 were comparable to Vorinostat in the presence of β‐D‐glucuronidase, but were higher than 10 μM in the absence of β‐D‐glucuronidase. Therefore, T1 and T2 are promising candidates for in vivo investigations with high potential to be the target water‐soluble prodrugs. IC50 values of Belinostat derivatives T3 and T4 were not affected by β‐D‐glucuronidase, but T3 and T4 had the excellent cell proliferation inhibition on Hut‐78. 相似文献
92.
组蛋白修饰模式的异常能导致基因表达的改变,这在肝癌的发生、发展中起重要作用。组蛋白修饰酶相关抑制剂可以抑制修饰酶的活性,逆转肝癌细胞异常的组蛋白修饰模式,从而达到治疗肿瘤的目的。对组蛋白修饰、相关修饰酶及其抑制剂的进一步研究,不仅有助于深入了解肝癌的发病机制,而且对于肝癌的诊断、防治和预后判断均有深远影响。 相似文献
93.
94.
Zunder RM Antczak AJ Berger JM Rine J 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(3):E144-E153
The histone chaperone Rtt106 binds histone H3 acetylated at lysine 56 (H3K56ac) and facilitates nucleosome assembly during several molecular processes. Both the structural basis of this modification-specific recognition and how this recognition informs Rtt106 function are presently unclear. Guided by our crystal structure of Rtt106, we identified two regions on its double-pleckstrin homology domain architecture that mediated histone binding. When histone binding was compromised, Rtt106 localized properly to chromatin but failed to deliver H3K56ac, leading to replication and silencing defects. By mutating analogous regions in the structurally homologous chromatin-reorganizer Pob3, we revealed a conserved histone-binding function for a basic patch found on both proteins. In contrast, a loop connecting two β-strands was required for histone binding by Rtt106 but was dispensable for Pob3 function. Unlike Rtt106, Pob3 histone binding was modification-independent, implicating the loop of Rtt106 in H3K56ac-specific recognition in vivo. Our studies described the structural origins of Rtt106 function, identified a conserved histone-binding surface, and defined a critical role for Rtt106:H3K56ac-binding specificity in silencing and replication-coupled nucleosome turnover. 相似文献
95.
Characterization of MADS-domain transcription factor complexes in Arabidopsis flower development 总被引:3,自引:0,他引:3
96.
The hinge region in androgen receptor control 总被引:2,自引:0,他引:2
Clinckemalie L Vanderschueren D Boonen S Claessens F 《Molecular and cellular endocrinology》2012,358(1):1-8
The region between the DNA-binding domain and the ligand-binding domain of nuclear receptors is termed the hinge region. Although this flexible linker is poorly conserved, diverse functions have been ascribed to it. For the androgen receptor (AR), the hinge region and in particular the (629)RKLKKL(634) motif, plays a central role in controlling AR activity, not only because it acts as the main part of the nuclear translocation signal, but also because it regulates the transactivation potential and intranuclear mobility of the receptor. It is also a target site for acetylation, ubiquitylation and methylation. The interplay between these different modifications as well as the phosphorylation at serine 650 will be discussed here. The hinge also has an important function in AR binding to classical versus selective androgen response elements. In addition, the number of coactivators/corepressors that might act via interaction with the hinge region is still growing. The importance of the hinge region is further illustrated by the different somatic mutations described in patients with androgen insensitivity syndrome and prostate cancer. In conclusion, the hinge region serves as an integrator for signals coming from different pathways that provide feedback to the control of AR activity. 相似文献
97.
The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells 总被引:1,自引:0,他引:1
Dan L Klimenkova O Klimiankou M Klusman JH van den Heuvel-Eibrink MM Reinhardt D Welte K Skokowa J 《Haematologica》2012,97(4):551-559
Background
Inhibitors of nicotinamide phosphoribosyltransferase have recently been validated as therapeutic targets in leukemia, but the mechanism of leukemogenic transformation downstream of this enzyme is unclear.Design and Methods
Here, we evaluated whether nicotinamide phosphoribosyltransferase’s effects on aberrant proliferation and survival of myeloid leukemic cells are dependent on sirtuin and delineated the downstream signaling pathways operating during this process.Results
We identified significant upregulation of sirtuin 2 and nicotinamide phosphoribosyltransferase levels in primary acute myeloid leukemia blasts compared to in hematopoietic progenitor cells from healthy individuals. Importantly, specific inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 significantly reduced proliferation and induced apoptosis in human acute myeloid leukemia cell lines and primary blasts. Intriguingly, we found that protein kinase B/AKT could be deacetylated by nicotinamide phosphoribosyltransferase and sirtuin 2. The anti-leukemic effects of the inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 were accompanied by acetylation of protein kinase B/AKT with subsequent inhibition by dephosphorylation. This leads to activation of glycogen synthase kinase-3 β via diminished phosphorylation and, ultimately, inactivation of β-catenin by phosphorylation.Conclusions
Our results provide strong evidence that nicotinamide phosphoribosyltransferase and sirtuin 2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the protein kinase B/AKT/ glycogen synthase kinase-3 β/β-catenin pathway is a target for inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 and, thereby, leukemia cell proliferation. 相似文献98.
Recent studies have shown an association between gene alterations by epigenetic mechanisms and suicidal behavior. These epigenetic mechanisms are mitotically, and in some cases meiotically, heritable changes in the genome through non-DNA sequence coding processes that alter gene expression as a result of variable changes in environmental stimuli. Genome-wide association studies have been inconsistent in elucidating the association between genes and suicidal behavior, thereby making the heritability of suicidal behavior is unclear. However, recent epigenetic studies have provided evidence that epigenetic mechanisms could deliver the missing link between the heritability of suicidal behavior and the interaction between environment and the genome. The present review provides an in-depth discussion of epigenetic mechanisms that may regulate gene expression in suicidal behavior. The findings of current epigenetic studies on suicidal behavior will also be discussed considering future epigenome-wide association studies on elucidating the contributions of environment and genome on suicidal behavior. 相似文献
99.
100.
Katrina Tatton‐Brown Anne Murray Sandra Hanks Jenny Douglas Ruth Armstrong Siddharth Banka Lynne M. Bird Carol L. Clericuzio Valerie Cormier‐Daire Tom Cushing Frances Flinter Marie‐Line Jacquemont Shelagh Joss Esther Kinning Sally Ann Lynch Alex Magee Vivienne McConnell Ana Medeira Keiichi Ozono Michael Patton Julia Rankin Debbie Shears Marleen Simon Miranda Splitt Volker Strenger Kyra Stuurman Clare Taylor Hannah Titheradge Lionel Van Maldergem I. Karen Temple Trevor Cole Sheila Seal Childhood Overgrowth Consortium Nazneen Rahman 《American journal of medical genetics. Part A》2013,161(12):2972-2980