Saccharomyces cerevisiae has proven to be a useful model organism for the study of telomerase, a specialized cellular reverse transcriptase that helps maintain genomic stability by adding telomeric ...DNA repeats to the ends of chromosomes. Yeast telomerase is thought to be a holoenzyme containing Est2p and
TLC1 RNA, the catalytic subunit and its intrinsic template, respectively, as well as the
TLC1-RNA-associated factors Est1p and Est3p. Cdc13p, a sequence-specific telomere-DNA-binding protein, is also required for action
in vivo. A current model for telomerase regulation is that telomere-associated Cdc13p binds Est1p, thereby recruiting telomerase. However, recent chromatin immunoprecipitation experiments suggest an alternate role for Est1p in activating Est2p–
TLC1-RNA that is already bound to the telomere. Three models for Est1p activation are presented.
Dimerization of TFIID When Not Bound to DNA Andrew K. P. Taggart; Pugh, B. Franklin
Science (American Association for the Advancement of Science),
05/1996, Letnik:
272, Številka:
5266
Journal Article
Recenzirano
For unknown reasons, the eukaryotic transcription factor TFIID inefficiently recognizes promoters. Human TFIID was found to form highly specific homodimers that must dissociate before DNA binding. ...TFIID dimers formed through self-association of the TATA-binding polypeptide (TBP) subunit and could be immunoprecipitated with antibodies to TAF$_{II}$250, the core subunit of TFIID. Chemical cross-linking experiments in HeLa cells revealed the presence of TBP dimers in vivo. These findings suggest that dimerization through TBP is the physiological state of TFIID when not bound to DNA. Thus, the inefficiency of TFIID binding to a promoter may be partly attributable to the competitive effect of dimerization.
Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at ...lowering free fatty acids in vitro and in vivo.
Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at lowering free fatty acids in vitro and in vivo.
The heterodimeric Ku complex affects telomere structure in diverse organisms. We report here that in the absence of Ku, the catalytic subunit of telomerase, Est2p, was not telomere-associated in G1 ...phase, and its association in late S phase was decreased. The telomere association of Est1p, a telomerase component that binds telomeres only in late S phase, was also reduced in the absence of Ku. The effects of Ku on telomerase binding require a 48-nucleotide (nt) stem-loop region of TLC1 telomerase RNA. Ku interacts with TLC1 RNA via this 48-nt region throughout the cell cycle, but this interaction was reduced after telomere replication. These data support a model in which Ku recruits telomerase to telomeres in G1 phase when telomerase is inactive and promotes telomerase-mediated telomere lengthening in late S phase.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A series of cycloalkene acid-based niacin receptor agonists were designed and synthesized. Several compounds that were potent against the niacin receptor, with enhanced cytochrome P450 selectivity ...against subtypes CYP2C8and CYP2C9 and had improved oral exposure in mice were identified.
The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.
A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity niacin receptor GPR109A. The structure–activity relationship (SAR) studies were aimed to ...improve activity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition, reduce serum shift and improve pharmacokinetic (PK) profiles.
A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity niacin receptor GPR109A. The structure–activity relationship (SAR) studies were aimed to improve activity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition, reduce serum shift and improve pharmacokinetic (PK) profiles.
A urea class of high affinity niacin receptor agonists was discovered. Compound
1a displayed good PK, better in vivo efficacy in reducing FFA in mouse than niacin, and no vasodilation in a mouse ...model. Compound
1q also demonstrated equal affinity to GPR109A as niacin.
A urea class of high affinity niacin receptor agonists was discovered. Compound
1a displayed good PK, better in vivo efficacy in reducing FFA in mouse than niacin, and no vasodilation in a mouse model. Compound
1q demonstrated equal affinity to GPR109A as niacin.
GPR109A is the receptor mediating both the antilipolytic and vasodilatory effects of nicotinic acid. In order to develop agonists for GPR109A with improved therapeutic indices we have sought to ...optimize animal models that evaluate both nicotinic acid-mediated inhibition of lipolysis and stimulation of vasodilatation. The rat and the dog have previously been used to study the antilipolytic effects of nicotinic acid, but no optimal vasodilatation model exits in either species.
We have developed a vasodilatation model in the rat that measures changes in ear perfusion using laser Doppler flowmetry. In the dog, we have developed a model of vasodilatation measuring changes in red color values in the ear, using a spectrocolorimeter. Effects of GPR109A agonists on lipolysis were measured in both species after oral dosing of compounds, and measuring plasma levels of free fatty acids.
In both rat and dog, GPR109A agonists induce dose- and time-dependent vasodilatation, similar to that observed in humans. Vasodilatation is inhibited in both species with cyclooxygenase inhibitors or a specific DP1 receptor antagonist, indicating that, as in man, nicotinic acid-induced vasodilatation in rats and dogs is mainly mediated by the release of PGD
2.
Our results show that both rat and dog are useful models for the characterization of GPR109A agonists. A therapeutic index for GPR109A agonists can be calculated in either species.
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