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Query: HUMANGGP:040116 (histone)
 44,835 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histones constitute the protein core around which DNA is coiled to form the basic structural unit of the chromosome known as the nucleosome. Because of the large amount of new histone needed during chromosome replication, the synthesis of histone and DNA is regulated in a complex manner. During RNA transcription and DNA replication, the basic nucleosomal structure as well as interactions between nucleosomes must be greatly altered to allow access to the appropriate enzymes and factors. The presence of extensive and varied post-translational modifications to the otherwise highly conserved histone primary sequences provides obvious opportunities for such structural alterations, but despite concentrated and sustained effort, causal connections between histone modifications and nucleosomal functions are not yet elucidated.
CRC Crit Rev Biochem 1986
PMID:Histones and their modifications. 351 76

A priori considerations and the concept of the sequence-dependent local curving of the DNA axis. Experimental evidence: electric dichroism (relaxation time measurements); anomalous electrophoretic mobility and gel-filtration of some restriction fragments of DNA; one-sided binding of the nucleosomal DNA to the mica surface. Theoretical predictions concerning the nucleotide sequences of the curved DNA. Discovery of the dinucleotide periodicity in the chromatin DNA. The sequence periodicity as a tool for mapping of the nucleosomes along the sequences. Preferential binding of the histone octamers to the curved pieces of DNA--sequence analysis predictions and comparison with experiments: Theoretical and experimental estimates of the tilt and roll angles for different combinations of the neighboring base-pairs. Inherent sequence-dependent curvature and apparent persistence length of DNA.
CRC Crit Rev Biochem 1985
PMID:Curved DNA. 390 55

The poly(A) sequence is added to 3' termini of nuclear RNA segments destined to become part of the mRNA, and may play an essential role in the selection of these segments. It appears to be required for at least some of the splicing events involved in mRNA processing. In the cytoplasm, the poly(A) segment is the target of a degradation process which causes its gradual shortening, and leads to a heterogeneous steady-state poly(A)-size distribution. Complete loss of the poly(A) is probably followed by inactivation of the mRNA, since chains depleted of poly(A) do not accumulate in the cells. A role for this sequence in the promotion of mRNA stability is suggested by the behavior of globin mRNA depleted of poly(A) after injection into frog oocytes. The poly(A) shortening process may be part of the mRNA inactivation mechanism, as indicated by the greater sensitivity to degradation of the poly(A) of some short-lived mRNAs. However, the stochastic mRNA decay implies that new and old mRNA chains, with long and short poly(A) segments, respectively are equally susceptible to inactivation. The poly(A)-lacking histone mRNAs are stable only in cells engaged in DNA replication. Present knowledge favors a role for poly(A) in the control of mRNA stability. Loss of this sequence could be controlled through modulation of poly(A)-protein interactions or through masking of a sequence directly adjacent to the poly(A). In the nucleus, the poly(A) sequence could also serve as stabilizing agent, but, in addition, it might interact with the splicing machinery.
CRC Crit Rev Biochem 1981
PMID:The Role of the poly(A) sequence in mammalian messenger RNA. 611 19

In vitro, for animal cells generally, butyrate at millimolar concentrations is an inhibitor of growth. In vivo, however, colonocytes are able to grow in the environment of about 20 mM butyrate produced by bacterial fermentation on the luminal side of the colonic epithelium. An in vivo increase of the butyrate supply results in growth stimulation of cells in the colonic crypts. This discrepancy, namely, that in cell cultures butyrate is an inhibitor of growth, whereas in vivo it has a trophic effect, is the so called in vivo paradox of butyrate. In the present review it is pointed out that butyrate is an inhibitor of histone deacetylases and there is sufficient evidence for hyperacetylation being the mechanism of the in vitro growth-inhibiting effect of butyrate. As within animal cells hyperacetylation has to occur at a certain butyrate concentration (1-10 mM), it is postulated that the in vivo lack of inhibition and 'paradoxical' stimulation of growth is a result of a low intracellular steady state concentration of butyrate in the lower layers of the crypt in spite of the much higher butyrate concentration on the luminal side. As butyrate is the preferential source of energy for colonocytes, the in vivo trophic effect is not paradoxical, when in spite of an increase of the butyrate concentration in stool, the intracellular butyrate concentration of intestinal epithelial cells still remains below the inhibiting level. For mature non-dividing colonocytes which are programmed for apoptosis, there is no difference between the observations made in vitro or in vivo. Furthermore, recent developments are discussed which suggest that cyclo-oxygenase-2 may play an essential role in colonic carcinogenesis. Cyclo-oxygenase-2 is found to be expressed in most colorectal carcinomas, but not in normal non-transformed intestinal epithelial cells (DeWitt and Smith, 1995). Cyclo-oxygenase-2 overexpression makes intestinal epithelial cells resistant to butyrate-induced apoptosis (Tsujii and DuBois, 1995). This escape from butyrate-induced apoptosis appears to be an essential prerequisite for the development of colorectal cancer and suggests a functional role of butyrate in growth, differentiation and programmed cell death of colonic epithelial cells.
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PMID:Butyrate, aspirin and colorectal cancer. 889 58

Aneuploidy is the hallmark of many human cancers. Recent work has strongly suggested that chromosome missegregation during mitosis is the main cause of aneuploidy and contributes to oncogenesis. Centromere protein (CENP)-A is the centromere-specific histone-H3-like variant essential for centromere structure and function. It plays a central role in the assembly of the protein complex, termed kinetochore, which is indispensable for equal chromosome segregation. In this study, we demonstrate that the kinetochore protein CENP-A was overexpressed in all of 11 primary human colorectal cancer tissues. CENP-A mRNA was also up-regulated, indicating that overexpression of CENP-A occurred at the transcriptional level. Immunostaining with anti-CENP-A antibodies showed increased CENP-A signals in the tumor cells. Moreover, coimmunostaining of CENP-B, a centromere-associated DNA binding protein, with CENP-A showed mistargeting of CENP-A to noncentromeric chromatin in the tumor cells. These results suggest that overexpression of CENP-A could play an important role for aneuploidy in colorectal cancers.
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PMID:Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. 1283 35

Sulforaphane (SFN), a compound found at high levels in broccoli and broccoli sprouts, is a potent inducer of phase 2 detoxification enzymes and inhibits tumorigenesis in animal models. SFN also has a marked effect on cell cycle checkpoint controls and cell survival and/or apoptosis in various cancer cells, through mechanisms that are poorly understood. We tested the hypothesis that SFN acts as an inhibitor of histone deacetylase (HDAC). In human embryonic kidney 293 cells, SFN dose-dependently increased the activity of a beta-catenin-responsive reporter (TOPflash), without altering beta-catenin or HDAC protein levels. Cytoplasmic and nuclear extracts from these cells had diminished HDAC activity, and both global and localized histone acetylation was increased, compared with untreated controls. Studies with SFN and with media from SFN-treated cells indicated that the parent compound was not responsible for the inhibition of HDAC, and this was confirmed using an inhibitor of glutathione S-transferase, which blocked the first step in the metabolism of SFN, via the mercapturic acid pathway. Whereas SFN and its glutathione conjugate (SFN-GSH) had little or no effect, the two major metabolites SFN-cysteine and SFN-N-acetylcysteine were effective HDAC inhibitors in vitro. Finally, several of these findings were recapitulated in HCT116 human colorectal cancer cells: SFN dose-dependently increased TOPflash reporter activity and inhibited HDAC activity, there was an increase in acetylated histones and in p21(Cip1/Waf1), and chromatin immunoprecipitation assays revealed an increase in acetylated histones bound to the P21 promoter. Collectively, these findings suggest that SFN may be effective as a tumor-suppressing agent and as a chemotherapeutic agent, alone or in combination with other HDAC inhibitors currently undergoing clinical trials.
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PMID:A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. 1531 18

Allelic imbalance (AI) on chromosome arm 22q has been detected in 20%-40% of colorectal cancers, suggesting that this chromosome arm has a tumor-suppressor gene involved in colorectal carcinogenesis. Recently, we isolated a candidate tumor-suppressor gene, MYO18B, at 22q12.1, that is deleted, mutated, and hypermethylated in more than 50% of lung cancers. In the present study, we analyzed genetic and epigenetic alterations of the MYO18B gene in colorectal cancers. AI at the MYO18B locus was detected in 16 of 43 (40%) informative cases. Mutations of the MYO18B gene were detected in 2 of 11 (18%) cell lines and 1 of 47 (2%) surgical specimens. Nine of 11 (82%) cell lines showed reduced MYO18B expression, which was restored in all 9 by treatment with 5-aza-2'-deoxycytidine and/or trichostatin A (TSA). Although hypermethylation of the promoter CpG island for MYO18B was not detected, a significant correlation was observed between the level of MYO18B expression and the level of acetylation of histones H3 and H4 in 6 cell lines with and without TSA treatment. Thus, it was suggested that MYO18B is inactivated in a considerable fraction of colorectal cancers by several mechanisms, especially silencing by histone deacetylation and/or AI. Furthermore, restoration of MYO18B expression in colorectal cancer cell lines HT29 and DLD-1 suppressed anchorage-independent growth, whereas it did not affect the growth rate in vitro. These results suggest that genetic and epigenetic inactivation of the MYO18B gene play an important role in colorectal carcinogenesis.
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PMID:Genetic and epigenetic alterations of the candidate tumor-suppressor gene MYO18B, on chromosome arm 22q, in colorectal cancer. 1575 Oct 41

Aberrant activation and upregulation of the Wnt pathway is a key feature of many cancers. Wnt antagonists have recently attracted wide attention. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist that can bind to Wnt proteins directly and inhibit Wnt signaling pathway. It has been reported that WIF-1 expression is down regulated in several solid tumors and that WIF-1 is silenced by promoter hypermethylation in lung and colorectal cancer. By using RT-PCR, bisulfite sequence analysis, and methylation-specific PCR, we analysed expression and methylation of WIF-1 in cancer cell lines and freshly resected cancer tissues of the esophagus, stomach, colorectum, and pancreas. Downregulation of WIF-1 mRNA expression was observed in 61 (91.0%) of 67 cancer cell lines, 16 (80.0%) of 20 esophageal, 23 (74.2%) of 31 gastric, 41 (82.0%) of 50 colorectal, and six (75.0%) of eight pancreatic cancer tissues. Downregulation of WIF-1 expression was also observed at protein level. No significant association between WIF-1 downregulation and clinicopathological characteristics was found, suggesting that downregulation of WIF-1 expression is an early event in carcinogenesis of these cancers. Indeed, downregulation of WIF-1 expression was observed in 32 (72.7%) of 44 colorectal adenoma tissues and 18 (78.2%) of 23 early mucosal or submucosal colorectal carcinoma tissues. CpG island hypermethylation in the WIF-1 promoter region correlated with downregulation of WIF-1 expression in cancer cell lines and tissues. Treatment with demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), restored WIF-1 expression in cancer cell lines. A combined treatment of 5-aza-dC and a histone deacetylase inhibitor, trichostatinA, restored WIF-1 expression synergistically, indicating the role of cytosine methylation and histone deacetylation in the silencing of the WIF-1 gene. Transfection of the WIF-1 gene construct into TE-1 esophageal cancer cell lines or SW48 colon cancer cell lines lacking WIF-1 expression resulted in a significant inhibition on colony formation, cell proliferation, anchorage-independent growth in soft agar. TOPflash assay showed WIF-1 inhibits Wnt canonical signaling in these cell lines. These results suggest tumor suppressive function of WIF-1, due to its ability to inhibit Wnt signaling. Our results suggest that WIF-1 silencing due to promoter hypermethylation is an important mechanism underlying aberrant activation of the Wnt signaling pathway in carcinogenesis of the digestive organs. Modulation of the Wnt pathway, through reversal of WIF-1 silencing by demethylating agents, is a potential target for treatment and/or prevention of gastrointestinal cancers.
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PMID:Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers. 1600 17

There is evidence that consumption of certain dietary ingredients may favourably modulate biotransformation of carcinogens. Associated with this is the hypothesis that the risk for developing colorectal cancer could be reduced, since its incidence is related to diet. Two main groups of biotransformation enzymes metabolize carcinogens, namely Phase I enzymes, which convert hydrophobic compounds to more water-soluble moieties, and Phase II enzymes (e.g. glutathione S-transferases [GST]), which primarily catalyze conjugation reactions. The conjugation of electrophilic Phase I intermediates with glutathione, for instance, frequently results in detoxification. Several possible colon carcinogens may serve as substrates for GST isoenzymes that can have marked substrate specificity. The conjugated products could be less toxic/genotoxic if GSTs are induced, thereby reducing exposure. Thus, numerous studies have shown that the induction of GSTs by antioxidants enables experimental animals to tolerate exposure to carcinogens. One important mechanism of GST induction involves an antioxidant-responsive response element (ARE) and the transcription factor nuclear factor E2-related factor 2 (Nrf2), which is bound to the Kelch-like ECH associated protein 1 (Keap1) in the cytoplasm. Antioxidants may disrupt the Keap-Nrf2 complex, allowing Nrf2 to translocate to the nucleus and mediate expression of Phase II genes via interaction with the ARE. GSTs are also induced by butyrate, a product of gut flora-derived fermentation of plant foods, which may act via different mechanisms, e.g. by increasing histone acetylation. GSTs are expressed with high inter-individual variability in human colonocytes, which points to large differences in cellular susceptibility to xenobiotics. Enhancing expression of GSTs in human colon tissue could therefore contribute to reducing cancer risks. However, it has not been demonstrated in humans that this mechanism is associated with cancer prevention. In the future, it will be useful to determine GSTs during dietary intervention studies to enhance our understanding of this protective mechanism.
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PMID:Modulation of xenobiotic metabolising enzymes by anticarcinogens -- focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis. 1608 18

Colorectal cancer is the third leading cause of cancer-related death in both men and woman in industrialized countries. Major advances have been made in our understanding of molecular events leading to formation of adenomatous polyps and cancer. Most colorectal cancers are sporadic, but a significant proportion (5-6%) has a clear genetic background. It is now widely accepted that colorectal carcinogenesis is a multistep process involving the inactivation of a variety of tumor-suppressor and DNA-repair genes and simultaneous activation of certain oncogenes. In addition, epigenetic alterations through aberrant promoter methylation and histone modification have been found to play a major role in the evolution and progression of a large proportion of sporadic colon cancers. Consequently, it is now apparent that individual colorectal cancers may evolve through diverse molecular pathways. In this article, the authors have summarized the current knowledge of molecular pathogenesis in common hereditary syndromes and sporadic forms of colorectal cancer. Novel molecular diagnostic tools for the early diagnosis and prevention of colorectal cancer that have emerged from these insights are discussed.
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PMID:Molecular pathogenesis of colorectal cancer: implications for molecular diagnosis. 1620 96


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