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61.
A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm 总被引:13,自引:0,他引:13
Kumar R Wang RA Mazumdar A Talukder AH Mandal M Yang Z Bagheri-Yarmand R Sahin A Hortobagyi G Adam L Barnes CJ Vadlamudi RK 《Nature》2002,418(6898):654-657
Oestrogen receptor (ER) is a good prognostic marker for the treatment of breast cancers. Upregulation of metastatic tumour antigen 1 (MTA1) is associated with the invasiveness and metastatic potential of several human cancers and acts as a co-repressor of nuclear ER-alpha. Here we identify a naturally occurring short form of MTA1 (MTA1s) that contains a previously unknown sequence of 33 amino acids with an ER-binding motif, Leu-Arg-Ile-Leu-Leu (LRILL). MTA1s localizes in the cytoplasm, sequesters ER in the cytoplasm, and enhances non-genomic responses of ER. Deleting the LRILL motif in MTA1s abolishes its co-repressor function and its interaction with ER, and restores nuclear localization of ER. Dysregulation of human epidermal growth factor receptor-2 in breast cancer cells enhances the expression of MTA1s and the cytoplasmic sequestration of ER. Expression of MTA1s in breast cancer cells prevents ligand-induced nuclear translocation of ER and stimulates malignant phenotypes. MTA1s expression is increased in human breast tumours with no or low nuclear ER. The regulation of the cellular localization of ER by MTA1s represents a mechanism for redirecting nuclear receptor signalling by nuclear exclusion. 相似文献
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Hon WC Wilson MI Harlos K Claridge TD Schofield CJ Pugh CW Maxwell PH Ratcliffe PJ Stuart DI Jones EY 《Nature》2002,417(6892):975-978
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Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells 总被引:7,自引:0,他引:7
The mechanism of disease-associated trinucleotide repeat instability involves cis-acting factors (cis-elements) in the vicinity of the repeat, but the nature of these elements is unknown. One cis-element may be the location of the replication origin relative to the repeat. We have used an SV40 DNA replication system to investigate the effect of the location of replication initiation on (CTG)(n)*(CAG)(n) stability in primate cells. Depending on the distance between the SV40 replication origin and the repeat tract, templates with 79 repeats yield predominantly expansions or predominantly deletions or remain intact. All templates with 17 repeats are stable. Thus, cis-elements that affect the sites of Okazaki fragment initiation relative to the repeat are crucial determinants of instability. This model system recapitulates the bias for expansions observed in many of the diseases associated with trinucleotide repeats. Our results might explain the variable amounts of CTG/CAG instability that are observed in different chromosomal contexts. 相似文献
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Genetic cost of reproductive assurance in a self-fertilizing plant 总被引:16,自引:0,他引:16
The transition from outcrossing to self-fertilization is one of the most common evolutionary trends in plants. Reproductive assurance, where self-fertilization ensures seed production when pollinators and/or potential mates are scarce, is the most long-standing and most widely accepted explanation for the evolution of selfing, but there have been few experimental tests of this hypothesis. Moreover, many apparently adaptive floral mechanisms that ensure the autonomous production of selfed seed might use ovules that would have otherwise been outcrossed. This seed discounting is costly if selfed offspring are less viable than their outcrossed counterparts, as often happens. The fertility benefit of reproductive assurance has never been examined in the light of seed discounting. Here we combine experimental measures of reproductive assurance with marker-gene estimates of self-fertilization, seed discounting and inbreeding depression to show that, during 2 years in 10 Ontario populations of Aquilegia canadensis (Ranunculaceae), reproductive assurance through self-fertilization increases seed production, but this benefit is greatly outweighed by severe seed discounting and inbreeding depression. 相似文献
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Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms 总被引:39,自引:0,他引:39
Barouch LA Harrison RW Skaf MW Rosas GO Cappola TP Kobeissi ZA Hobai IA Lemmon CA Burnett AL O'Rourke B Rodriguez ER Huang PL Lima JA Berkowitz DE Hare JM 《Nature》2002,416(6878):337-339
Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca2+ channels but stimulates sarcoplasmic reticulum (SR) Ca2+ release, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit beta-adrenergic-induced inotropy. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro, suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both NOS1-/- and NOS3-/- mice develop age-related hypertrophy, although only NOS3-/- mice are hypertensive. NOS1/3-/- double knockout mice have suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function. 相似文献
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