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1.
Histone acetylation and disease 总被引:18,自引:0,他引:18
S. Timmermann H. Lehrmann A. Polesskaya A. Harel-Bellan 《Cellular and molecular life sciences : CMLS》2001,58(5-6):728-736
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Biological functions of the ING family tumor suppressors 总被引:11,自引:0,他引:11
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Apoptosis is a fundamental process for metazoan development. It is also relevant to the pathophysiology of immune diseases and cancers and to the outcome of cancer chemotherapies, as well as being a target for cancer therapies. Apoptosis involves intrinsic pathways typically initiated by DNA damaging agents and engaging mitochondria, and extrinsic pathways typically initiated by “death receptors” and their ligands TRAIL and TNF at the cell surface. Recently, we discovered the apoptotic ring, which microscopically looks like a nuclear annular staining early in apoptosis. This ring is, in three-dimensional space, a thick intranuclear shell consisting of epigenetic modifications including histone H2AX and DNA damage response (DDR) proteins. It excludes the DNA repair factors usually associated with γ-H2AX in the DDR nuclear foci. Here, we summarize our knowledge of the apoptotic ring, and discuss its biological and pathophysiological relevance, as well as its value as a potential pharmacodynamic biomarker for anticancer therapies. 相似文献
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Dewei Chen Wenxiang Gao Shouxian Wang Bing Ni Yuqi Gao 《Cellular and molecular life sciences : CMLS》2017,74(20):3789-3808
Pulmonary arterial hypertension (PAH) is characterized by persistent pulmonary vasoconstriction and pulmonary vascular remodeling. The pathogenic mechanisms of PAH remain to be fully clarified and measures of effective prevention are lacking. Recent studies; however, have indicated that epigenetic processes may exert pivotal influences on PAH pathogenesis. In this review, we summarize the latest research findings regarding epigenetic regulation in PAH, focusing on the roles of non-coding RNAs, histone modifications, ATP-dependent chromatin remodeling and DNA methylation, and discuss the potential of epigenetic-based therapies for PAH. 相似文献
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Chen Liang Si Shi Qingcai Meng Dingkong Liang Shunrong Ji Bo Zhang Yi Qin Jin Xu Quanxing Ni Xianjun Yu 《Cellular and molecular life sciences : CMLS》2018,75(6):1001-1012
Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies, with approximately 20–30% of PDAC patients receiving the surgical resection with curative intent. Although many studies have focused on finding ideal “drug chaperones” that facilitate and/or potentiate the effects of gemcitabine (GEM) in pancreatic cancer, a significant benefit in overall survival could not be demonstrated for any of these combination therapies in PDAC. Given that pancreatic cancer is characterized by desmoplasia and the dual biological roles of stroma in pancreatic cancer, we reassess the importance of stroma in GEM-based therapeutic approaches in light of current findings. This review is focused on understanding the role of stromal components in the extrinsic resistance to GEM and whether anti-stroma therapies have a positive effect on the GEM delivery. This work contributes to the development of novel and promising combination GEM-based regimens that have achieved significant survival benefits for the patients with pancreatic cancer. 相似文献
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Feyruz V. Rassool Alan E. Tomkinson 《Cellular and molecular life sciences : CMLS》2010,67(21):3699-3710
A major challenge in cancer treatment is the development of therapies that target cancer cells with little or no toxicity
to normal tissues and cells. Alterations in DNA double strand break (DSB) repair in cancer cells include both elevated and
reduced levels of key repair proteins and changes in the relative contributions of the various DSB repair pathways. These
differences can result in increased sensitivity to DSB-inducing agents and increased genomic instability. The development
of agents that selectively inhibit the DSB repair pathways that cancer cells are more dependent upon will facilitate the design
of therapeutic strategies that exploit the differences in DSB repair between normal and cancer cells. Here, we discuss the
pathways of DSB repair, alterations in DSB repair in cancer, inhibitors of DSB repair and future directions for cancer therapies
that target DSB repair. 相似文献
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Silencing of DNA repair genes plays a critical role in the development of the cancer because these genes, functioning normally, would prevent the accumulation of mutations leading to carcinogenesis. Epigenetic gene silencing is an alternative mechanism to genetic gene aberration, inactivating those genes in cancer. DNA methylation and histone modification are the major factors for epigenetic regulation of gene expression. Here, we describe recent advances in understanding of epigenetic silencing of DNA repair genes and their epigenetic mechanisms involving DNA methylation and histone modification. 相似文献
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Rosy El Ramy Najat Magroun Nadia Messadecq Laurent R. Gauthier François D. Boussin Ullas Kolthur-Seetharam Valérie Schreiber Michael W. McBurney Paolo Sassone-Corsi Françoise Dantzer 《Cellular and molecular life sciences : CMLS》2009,66(19):3219-3234
Poly(ADP-ribose) polymerase-1 (Parp-1) and the protein deacetylase SirT1 are two of the most effective NAD+-consuming enzymes in the cell with key functions in genome integrity and chromatin-based pathways. Here, we examined the
in vivo crosstalk between both proteins. We observed that the double disruption of both genes in mice tends to increase late
post-natal lethality before weaning consistent with important roles of both proteins in genome integrity during mouse development.
We identified increased spontaneous telomeric abnormalities associated with decreased cell growth in the absence of either
SirT1 or SirT1 and Parp-1 in mouse cells. In contrast, the additional disruption of Parp-1 rescued the abnormal pericentric
heterochromatin, the nucleolar disorganization and the mitotic defects observed in SirT1-deficient cells. Together, these
findings are in favor of key functions of both proteins in cellular response to DNA damage and in the modulation of histone
modifications associated with constitutive heterochromatin integrity. 相似文献
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Duyilemi C. Ajonijebu Oualid Abboussi Vivienne A. Russell Musa V. Mabandla William M. U. Daniels 《Cellular and molecular life sciences : CMLS》2017,74(15):2735-2747
The detrimental effects of drug abuse are apparently not limited to individuals but may also impact the vulnerability of their progenies to develop addictive behaviours. Epigenetic signatures, early life experience and environmental factors, converge to influence gene expression patterns in addiction phenotypes and consequently may serve as mediators of behavioural trait transmission between generations. The majority of studies investigating the role of epigenetics in addiction do not consider the influence of social interactions. This shortcoming in current experimental approaches necessitates developing social models that reflect the addictive behaviour in a free-living social environment. Furthermore, this review also reports on the advancement of interventions for drug addiction and takes into account the emerging roles of histone deacetylase (HDAC) inhibitors in the etiology of drug addiction and that HDAC may be a potential therapeutic target at nucleosomal level to improve treatment outcomes. 相似文献
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Jessica L. Slack Corey P. Causey Paul R. Thompson 《Cellular and molecular life sciences : CMLS》2011,68(4):709-720
The recent approvals of anticancer therapeutic agents targeting the histone deacetylases and DNA methyltransferases have highlighted
the important role that epigenetics plays in human diseases, and suggested that the factors controlling gene expression are
novel drug targets. Protein arginine deiminase 4 (PAD4) is one such target because its effects on gene expression parallel
those observed for the histone deacetylases. We demonstrated that F- and Cl-amidine, two potent PAD4 inhibitors, display micromolar
cytotoxic effects towards several cancerous cell lines (HL-60, MCF7 and HT-29); no effect was observed in noncancerous lines
(NIH 3T3 and HL-60 granulocytes). These compounds also induced the differentiation of HL-60 and HT29 cells. Finally, these
compounds synergistically potentiated the cell killing effects of doxorubicin. Taken together, these findings suggest PAD4
inhibition as a novel epigenetic approach for the treatment of cancer, and suggest that F- and Cl-amidine are candidate therapeutic
agents for this disease. 相似文献
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L.A. Pile F.W.-H. Lee D.A. Wassarman 《Cellular and molecular life sciences : CMLS》2001,58(11):1715-1718
We examined the consequences of the deacetylase inhibitor trichostatin A (TSA) on the development of Drosophila melanogaster. When fed to flies, TSA caused lethality and delayed development at concentrations as low as 5 μM, had stronger effects on
males than females, and acted synergistically with mutations in the gene encoding the RPD3 deacetylase to cause notched wings,
but did not appear to affect a SINA signaling pathway that is normally repressed by the SIN3 corepressor. These findings suggest
that deacetylated histones play an important role in normal developmental progression and establish parameters for genetic
screens to dissect the role of deacetylases in this process.
Received 14 June 2001; received after revision 31 July 2001; accepted 21 August 2001 相似文献
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Shin JM Vagin O Munson K Kidd M Modlin IM Sachs G 《Cellular and molecular life sciences : CMLS》2008,65(2):264-281
Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration;
therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor
were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell
hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are
the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities.
Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of
a novel class of agents, the acid pump antagonists.
Received 30 May 2007; received after revision 15 August 2007; accepted 13 September 2007 相似文献
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David M. Wilson III Anton Simeonov 《Cellular and molecular life sciences : CMLS》2010,67(21):3621-3631
APE1 is a multifunctional protein that possesses several nuclease activities, including the ability to incise at apurinic/apyrimidinic
(AP) sites in DNA or RNA, to excise 3′-blocking termini from DNA ends, and to cleave at certain oxidized base lesions in DNA.
Pre-clinical and clinical data indicate a role for APE1 in the pathogenesis of cancer and in resistance to DNA-interactive
drugs, particularly monofunctional alkylators and antimetabolites. In an effort to improve the efficacy of therapeutic compounds,
such as temozolomide, groups have begun to develop high-throughput screening assays and to identify small molecule inhibitors
against APE1 repair nuclease activities. It is envisioned that such inhibitors will be used in combinatorial treatment paradigms
to enhance the efficacy of DNA-interactive drugs that introduce relevant cytotoxic DNA lesions. In this review, we summarize
the current state of the efforts to design potent and selective inhibitors against APE1 AP site incision activity. 相似文献
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Cristina Zahonero Pilar Sánchez-Gómez 《Cellular and molecular life sciences : CMLS》2014,71(18):3465-3488
Glioblastoma is a particularly resilient cancer, and while therapies may be able to reach the brain by crossing the blood–brain barrier, they then have to deal with a highly invasive tumor that is very resistant to DNA damage. It seems clear that in order to kill aggressive glioma cells more efficiently and with fewer side effects on normal tissue, there must be a shift from classical cytotoxic chemotherapy to more targeted therapies. Since the epidermal growth factor receptor (EGFR) is altered in almost 50 % of glioblastomas, it currently represents one of the most promising therapeutic targets. In fact, it has been associated with several distinct steps in tumorigenesis, from tumor initiation to tumor growth and survival, and also with the regulation of cell migration and angiogenesis. However, inhibitors of the EGFR kinase have produced poor results with this type of cancer in clinical trials, with no clear explanation for the tumor resistance observed. Here we will review what we know about the expression and function of EGFR in cancer and in particular in gliomas. We will also evaluate which are the possible molecular and cellular escape mechanisms. As a result, we hope that this review will help improve the design of future EGFR-targeted therapies for glioblastomas. 相似文献