AG10 CONSISTENTLY STABILIZES TRANSTHYRETIN TO A HIGH LEVEL IN BOTH WILD TYPE AND MUTANT AMYLOID CARDIOMYOPATHY: RESPONDER ANALYSES FROM A PHASE 2 CLINICAL TRIAL
Jonathan C. FoxStephen B. HeitnerRodney H. FalkMartha GroganDaniel JacobyDaniel P. JudgeMathew S. MaurerVan SelbySanjiv J. ShahRonald WittelesSatish RaoUma Sinha
2
Citation
0
Reference
10
Related Paper
Citation Trend
Keywords:
Wild type
Radial immunodiffusion
Amyloid (mycology)
Amyloid polyneuropathy
Cite
Citations (21)
It has been suggested that the dominant effect of mutant p53 on tumor progression may reflect the mutant protein binding to wild-type p53, with inactivation of suppressor function. To date, evidence for wild-type/mutant p53 complexes involves p53 from different species. To investigate wild-type/mutant p53 complexes in relation to natural tumor progression, we sought to identify intraspecific complexes, using murine p53. The mutant phenotype p53-246(0) was used because this phenotype is immunologically distinct from wild-type p53-246+ and thus permits immunological analysis for wild-type/mutant p53 complexes. The p53 proteins were derived from genetically defined p53 cDNAs expressed in vitro and also from phenotypic variants of p53 expressed in vivo. We found that the mutant p53 phenotype was able to form a complex with the wild type when the two p53 variants were cotranslated. When mixed in their native states (after translation), the wild-type and mutant p53 proteins did not exhibit any binding affinity for each other in vitro. Under identical conditions, complexes of wild-type human and murine p53 proteins were formed. For murine p53, both the wild-type and mutant p53 proteins formed high-molecular-weight complexes when translated in vitro. This oligomerization appeared to involve the carboxyl terminus, since truncated p53 (amino acids 1 to 343) did not form complexes. We suggest that the ability of the mutant p53 phenotype to complex with wild type during cotranslation may contribute to the transforming function of activated mutants of p53 in vivo.
Wild type
Cite
Citations (66)
<div>Abstract<p>The mechanisms for “gain-of-function” phenotypes produced by mutant p53s such as enhanced proliferation, resistance to transforming growth factor-β–mediated growth suppression, and increased tumorigenesis are not known. One theory is that these phenotypes are caused by novel transcriptional regulatory events acquired by mutant p53s. Another explanation is that these effects are a result of an imbalance of functions caused by the retention of some of the wild-type transcriptional regulatory events in the context of a loss of other counterbalancing activities. An analysis of the ability of DNA-binding domain mutants A138P and R175H, and wild-type p53 to regulate the expression levels of 6.9 × 10<sup>3</sup> genes revealed that the mutants retained only <5% of the regulatory activities of the wild-type protein. A138P p53 exhibited mostly retained wild-type regulatory activities and few acquired novel events. However, R175H p53 possessed an approximately equal number of wild-type regulatory events and novel activities. This is the first report that, after examination of the regulation of a large unfocused set of genes, provides data indicating that remaining wild-type transcriptional regulatory functions existing in the absence of counterbalancing activities as well as acquired novel events both contribute to the gain-of-function phenotypes produced by mutant p53s. However, mutant p53s are likely to be distinct in terms of the extent to which each mechanism contributes to their gain-of-function phenotypes.</p></div>
Wild type
Cite
Citations (0)
<div>Abstract<p>The mechanisms for “gain-of-function” phenotypes produced by mutant p53s such as enhanced proliferation, resistance to transforming growth factor-β–mediated growth suppression, and increased tumorigenesis are not known. One theory is that these phenotypes are caused by novel transcriptional regulatory events acquired by mutant p53s. Another explanation is that these effects are a result of an imbalance of functions caused by the retention of some of the wild-type transcriptional regulatory events in the context of a loss of other counterbalancing activities. An analysis of the ability of DNA-binding domain mutants A138P and R175H, and wild-type p53 to regulate the expression levels of 6.9 × 10<sup>3</sup> genes revealed that the mutants retained only <5% of the regulatory activities of the wild-type protein. A138P p53 exhibited mostly retained wild-type regulatory activities and few acquired novel events. However, R175H p53 possessed an approximately equal number of wild-type regulatory events and novel activities. This is the first report that, after examination of the regulation of a large unfocused set of genes, provides data indicating that remaining wild-type transcriptional regulatory functions existing in the absence of counterbalancing activities as well as acquired novel events both contribute to the gain-of-function phenotypes produced by mutant p53s. However, mutant p53s are likely to be distinct in terms of the extent to which each mechanism contributes to their gain-of-function phenotypes.</p></div>
Wild type
Loss function
Cite
Citations (0)
Site-directed mutants of the gene encoding wild-type Vitreoscilla hemoglobin were made that changed Tyr29 (B10) of the wild-type Vitreoscilla hemoglobin (VHb) to either Phe or Ala. The wild-type and the two mutant hemoglobins were expressed in Escherichia coli and purified to homogeneity. The binding of the two mutants to CO was essentially identical to that of wild-type VHb as determined by CO-difference spectra. Circular-dichroism spectra also showed the two mutants to be essentially the same as wild-type VHb regarding overall helicity. All three VHbs were crystallized and their structures were determined at resolutions of 1.7–1.9 Å, which are similar to that of the original wild-type structure determination. The Tyr29Phe mutant has a structure that is essentially indistinguishable from that of the wild type. However, the structure of the Tyr29Ala mutant has significant differences from that of the wild type. In addition, for the Tyr29Ala mutant it was possible to determine the positions of most of the residues in the D region, which was disordered in the originally reported structure of wild-type VHb as well as in the wild-type VHb structure reported here. In the Tyr29Ala mutant, the five-membered ring of proline E8 (Pro54) occupies the space occupied by the aromatic ring of Tyr29 in the wild-type structure. These results are discussed in the context of the proposed role of Tyr29 in the structure of the oxygen-binding pocket.
Cite
Citations (6)
It has been suggested that the dominant effect of mutant p53 on tumor progression may reflect the mutant protein binding to wild-type p53, with inactivation of suppressor function. To date, evidence for wild-type/mutant p53 complexes involves p53 from different species. To investigate wild-type/mutant p53 complexes in relation to natural tumor progression, we sought to identify intraspecific complexes, using murine p53. The mutant phenotype p53-246(0) was used because this phenotype is immunologically distinct from wild-type p53-246+ and thus permits immunological analysis for wild-type/mutant p53 complexes. The p53 proteins were derived from genetically defined p53 cDNAs expressed in vitro and also from phenotypic variants of p53 expressed in vivo. We found that the mutant p53 phenotype was able to form a complex with the wild type when the two p53 variants were cotranslated. When mixed in their native states (after translation), the wild-type and mutant p53 proteins did not exhibit any binding affinity for each other in vitro. Under identical conditions, complexes of wild-type human and murine p53 proteins were formed. For murine p53, both the wild-type and mutant p53 proteins formed high-molecular-weight complexes when translated in vitro. This oligomerization appeared to involve the carboxyl terminus, since truncated p53 (amino acids 1 to 343) did not form complexes. We suggest that the ability of the mutant p53 phenotype to complex with wild type during cotranslation may contribute to the transforming function of activated mutants of p53 in vivo.
Wild type
Cite
Citations (242)
Wild type
Conformational change
Cite
Citations (620)
Objective: Mutant-type and Wild-type ATP7B were transfected and expressed in skin fibroblasts Me32aT22/2L cell lines. Copper transport function of mutant-type and wild-type ATP7B were studied and made the basement for further gene therapy of hepatolenticular degeneration. Methods: pRc/CMV-WD containing cDNA of mutant-type or wild-type ATP7B was transfected into Me32aT22/2L cell using liposome transfection methods,respectively. Intracellular distribution of mutant-type and wild-type ATP7B were observed by immunofluorescence histochemistry methods and copper transport function was studied in copper incubation experiments. Results: Expression of ATB7B gene was detected and located around the nuclei in Me32aT22/2L cell. At 24 and 48 hours,in wild-type ATP7B group,copper/protein value is 335.33±49.86 and 477.38±30.95,respectively,however,606.14± 45.72 vs 901.84±53.18 in mutant-type ATP7B group. Significant statistical difference could be obtained (P 0.05). Conclusion: Wild-type ATP7B could transport intracellular redundant copper and mutant-type ATP7B lost this function. Mutant R778L gene is a pathogenic gene of hepatolenticular degeneration.
Wild type
Cite
Citations (0)
The chlorophyll content,photosynthetic rate,chlorophyll fluorescence kinetic parameters and single plant yield of a new xantha type rice mutant(Annongbiao 810S) and its wild type(Annong 810S) were comparatively studied.It was showed that: the total chlorophyll content in mutant was significantly lower than that of the wild type at the whole growth stage,the chlorophyll content in combination F1 from mutant had no difference with that in combination F1 from wild rice;the Chl a/Ch b ratio in mutant was higher than that of wild type;the net photosynthetic rate of the mutant at different stages was higher than that in the wild type;the FV/Fm,FV′/Fm′,φPS2,ETR2 and QP in the mutant were higher than that in the wild type,the QN was lower in the mutant;the yield of self-breed in the mutant was higher than that of the wild type,the test of F1 hybrid performance showed that the mutant had excellent combining ability.
Wild type
Cite
Citations (0)
Abstract The apical portions of the nonbudding mutant of Hydra viridis were induced to bud by grafting to them basal portions of wild type hydra of the same species. The induced buds had unusual developmental and morphogenetic properties that frequently showed characteristics of both wild type and mutant animals. The rate and extent of bud induction varied depending upon the body region of the wild type tissue grafted to mutant tissue. The gastric region induced the most buds at the highest rate. Induced buds containing cells from both the wild type and the nonbudding mutant were referred to as “heterocytes”. Wild type heterocytes were more like the mutant. Mutant heterocytes had regeneration properties characteristic of both the wild type and mutant animals depending upon how long they had been fed. The initial budding rates of the wild type heterocytes varied, but eventually all wild type heterocytes transformed into animals of mutant phenotype. These observations suggest that complex interactions are taking place in the heterocytes composed of cells derived from both the wild type and the nonbudding mutant.
Budding
Lernaean Hydra
Wild type
Cite
Citations (3)