isoforms
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- MeSH
- kardiomyocyty enzymologie fyziologie MeSH
- protein - isoformy klasifikace MeSH
- sodíko-draslíková ATPasa fyziologie MeSH
- Publikační typ
- přehledy MeSH
Metallothioneins (MTs) belong to a group of small cysteine-rich proteins that are ubiquitous throughout all kingdoms. The main function of MTs is scavenging of free radicals and detoxification and homeostating of heavy metals. In humans, 16 genes localized on chromosome 16 have been identified to encode four MT isoforms labelled by numbers (MT-1-MT-4). MT-2, MT-3 and MT-4 proteins are encoded by a single gene. MT-1 comprises many (sub)isoforms. The known active MT-1 genes are MT-1A, -1B, -1E, -1F, -1G, -1H, -1M and -1X. The rest of the MT-1 genes (MT-1C, -1D, -1I, -1J and -1L) are pseudogenes. The expression and localization of individual MT (sub)isoforms and pseudogenes vary at intra-cellular level and in individual tissues. Changes in MT expression are associated with the process of carcinogenesis of various types of human malignancies, or with a more aggressive phenotype and therapeutic resistance. Hence, MT (sub)isoform profiling status could be utilized for diagnostics and therapy of tumour diseases. This review aims on a comprehensive summary of methods for analysis of MTs at (sub)isoforms levels, their expression in single tumour diseases and strategies how this knowledge can be utilized in anticancer therapy.
- MeSH
- epigeneze genetická MeSH
- lidé MeSH
- metalothionein metabolismus MeSH
- nádory farmakoterapie genetika metabolismus MeSH
- protein - isoformy MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Východisko. Apolipoprotein E (apoE) je polymorfní protein hrající centrální úlohu v metabolismu plazmatických lipidů. Vyskytuje se běžně ve třech izoformách, které jsou kódovány třemi alelami označovanými e2, e3 a e4. V normální populaci se vyskytuje nejčastěji alela e3. Výskyt alel e2 a e4 je spojován s poruchami metabolismu lipoproteinů a dalšími chorobnými stavy. Cílem naší studie bylo stanovit frekvence jednotlivých alel u pacientů s různými typy hyperlipoproteinémií (HLP) a zjistit rozdíly v jejich distribuci ve srovnání s populačním vzorkem. Metody a výsledky. Genotyp apoE byl stanoven u 752 pacientů s primární HLP, kontrolní soubor tvořilo 291 osob náhodně vybraných z běžné české populace. Frekvence alel byly určeny pro skupiny pacientů s familiární hypercholesterolémií (FH), polygenní hypercholesterolémií (PHC), familiární kombinovanou hyperlipidémií (FCH) a u pacientů s HLP III. typu (III). U pacientů s HLP byla nalezena signifikantně vyšší frekvence alely e4 než u kontrolního souboru. U skupiny FH pacientů byla frekvence alely e2 nižší než u kontrolního souboru. U pacientů s PHC jsme nalezli signifikantně vyšší frekvenci alely e4 a nižší frekvenci e2. U skupiny pacientů s FCH se alelické frekvence nelišily od kontrolního souboru. Frekvence alely e2 u skupiny pacientů s HLP III. typu byla signifikantně vyšší než u kontrol. Závěry. Provedená studie potvrzuje existenci signifikantních rozdílů ve frekvencích jednotlivých alel kódujících izoformy apoE mezi pacienty s primární hyperlipoproteinémií a souborem náhodně vybraných osob z běžné popu- lace. Rozdíly v nalezených frekvencích naznačují různou míru vlivu polymorfismu apoE u jednotlivých typů hyperlipoproteinémií.
Background. Apolipoprotein E is a polymorphic protein playing a crucial role in the metabolism of plasma lipoproteins. Three alleles referred to as e2, e3 and e4 code for three common isoforms of apoE. The most frequent allele in the population at large is e3 allele. e2 and e4 alleles are connected with lipoprotein disorders as well as with other diseases. The aim of our study was to establish frequencies of apoE coding alleles in patients with different types of hyperlipidaemia (HLP) and to reveal differences in their distribution in comparison with the general population. Methods and Results. Therefore apoE genotype was assayed in 752 patients with primary HLP and 291 subjects randomly selected from the general Czech population. Allele frequencies were determined separately in a group of patients with familial hypercholesterolaemia (FH), polygenic hypercholesterolaemia (PHC), familial combined hyperlipidaemia (FCH) and in patients with type III. hyperlipidaemia (III). In patients with HLP a significantly higher frequency of e4 allele than in control subjects was found. In the group of FH patients frequency of the e2 allele was higher than in control subjects. In patients with PHC a significantly higher frequency of the e4 allele and lower frequency of the e2 allele were observed. In the group of FCH patients distribution of e alleles did not differ from the control group. Frequency of the e2 allele in patients with type III. hyperlipidaemia was significantly higher than in controls. Conclusions. We conclude that there exist significant differences in frequencies of apoE coding alleles between patients with primary hyperlipidaemia and a randomly selected population sample. The revealed differences in allelic distribution suggest that the impact of apoE polymorphism is not uniform in all types of hyperlipidaemia.
Yes-associated protein 1 (YAP1) is a transcriptional co-activator downstream of Hippo pathway. The pathway exerts crucial roles in organogenesis and its dysregulation is associated with the spreading of different cancer types. YAP1 gene encodes for multiple protein isoforms, whose specific functions are not well defined. We demonstrate the splicing of isoform-specific mRNAs is controlled in a stage- and tissue-specific fashion. We designed expression vectors encoding for the most-represented isoforms of YAP1 with either one or two WW domains and studied their specific signaling activities in YAP1 knock-out cell lines. YAP1 isoforms display both common and unique functions and activate distinct transcriptional programs, as the result of their unique protein interactomes. By generating TEAD-based transcriptional reporter cell lines, we demonstrate individual YAP1 isoforms display unique effects on cell proliferation and differentiation. Finally, we illustrate the complexity of the regulation of Hippo-YAP1 effector in physiological and in pathological conditions of the heart.
The objective of this study was to determine whether human auricular chondrocytes can also express ?--smooth muscle actin. Immunohistochemistry using monoclonal antibodies for ?-smooth actin, muscle-specific actin, ß-actin, S-100 protein, CD34, and desmin was performed on samples of human ear cartilage obtained from 20 individuals during a partial resection of the ear for different reasons. Moreover, the RT-PCR analysis of actin isoforms in auricular chondrocytes was performed. Approximately 60 % of the chondrocytes of the ear cartilage expressed ?-smooth muscle actin as demonstrated by immunohistochemistry in all the examined samples. Actin-positive chondrocytes occurred in both external subperichondrial layers of the auricular cartilage. This finding was confirmed by the RT-PCR technique. The knowledge of this fact could help us to better understand the chondrocyte changes occurring during the healing and transplantation of auricular cartilage. The question of whether it is necessary to refer to these predominating cells in ear cartilage as myochondrocytes is considered. This is the first report of an unusual immunophenotype and contractile potential for human auricular chondrocytes.
- MeSH
- aktiny genetika klasifikace MeSH
- antigeny CD34 genetika MeSH
- barvení a značení metody využití MeSH
- chondrocyty cytologie MeSH
- financování vládou MeSH
- lidé MeSH
- polymerázová řetězová reakce s reverzní transkripcí metody využití MeSH
- protein - isoformy genetika MeSH
- ušní chrupavka cytologie růst a vývoj MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
Cellular senescence is a hallmark of normal aging and aging-related syndromes, including the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), a rare genetic disorder caused by a single mutation in the LMNA gene that results in the constitutive expression of a truncated splicing mutant of lamin A known as progerin. Progerin accumulation leads to increased cellular stresses including unrepaired DNA damage, activation of the p53 signaling pathway and accelerated senescence. We previously established that the p53 isoforms ∆133p53 and p53β regulate senescence in normal human cells. However, their role in premature aging is unknown. Here we report that p53 isoforms are expressed in primary fibroblasts derived from HGPS patients, are associated with their accelerated senescence and that their manipulation can restore the replication capacity of HGPS fibroblasts. We found that in near-senescent HGPS fibroblasts, which exhibit low levels of ∆133p53 and high levels of p53β, restoration of Δ133p53 expression was sufficient to extend replicative lifespan and delay senescence, despite progerin levels and abnormal nuclear morphology remaining unchanged. Conversely, Δ133p53 depletion or p53β overexpression accelerated the onset of senescence in otherwise proliferative HGPS fibroblasts. Our data indicate that Δ133p53 exerts its role by modulating full-length p53 (FLp53) signaling to extend the replicative lifespan and promotes the repair of spontaneous progerin-induced DNA double-strand breaks (DSBs). We showed that Δ133p53 dominant-negative inhibition of FLp53 occurs directly at the p21/CDKN1A and miR-34a promoters, two p53 senescence-associated genes. In addition, Δ133p53 expression increased the expression of DNA repair RAD51, likely through upregulation of E2F1, a transcription factor that activates RAD51, to promote repair of DSBs. In summary, our data indicate that Δ133p53 modulates p53 signaling to repress progerin-induced early onset of senescence in HGPS cells. Therefore, restoration of ∆133p53 expression may be a novel therapeutic strategy to treat aging-associated phenotypes of HGPS in vivo.
- MeSH
- časové faktory MeSH
- fibroblasty patologie fyziologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- nádorový supresorový protein p53 genetika fyziologie MeSH
- poškození DNA genetika MeSH
- předčasné stárnutí genetika patologie MeSH
- progerie genetika patologie MeSH
- protein - isoformy fyziologie MeSH
- stárnutí buněk genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The p53 protein is a key tumor suppressor and the most commonly mutated and down-regulated protein in human tumors. It functions mainly through interaction with DNA, and p53 acts as a transcription factor that recognizes the so-called p53 target sites on the promoters of various genes. P53 has been shown to exist as many isoforms, including three C-terminal isoforms that are produced by alternative splicing. Because the C-terminal domain is responsible for sequence-nonspecific binding and regulation of p53 binding, we have analyzed DNA recognition by these C-terminal isoforms. Using atomic force microscopy, we show for the first time that all C-terminal isoforms recognize superhelical DNA. It is particularly noteworthy that a sequence-specific p53 consensus binding site is bound by p53α and β isoforms with similar affinities, whilst p53α shows higher binding to a quadruplex sequence than both p53β and p53γ, and p53γ loses preferential binding to both the consensus binding sequence and the quadruplex-forming sequence. These results show the important role of the variable p53 C-terminal amino acid sequences for DNA recognition.
Apolipoprotein E (APOE) is distributed across various human tissues and plays a crucial role in lipid metabolism. Recent investigations have uncovered an additional facet of APOE's functionality, revealing its role in host defense against bacterial infections. To assess the antibacterial attributes of APOE3 and APOE4, we conducted antibacterial assays using Pseudomonas aeruginosa and Escherichia coli. Exploring the interaction between APOE isoforms and lipopolysaccharides (LPSs) from E. coli, we conducted several experiments, including gel shift assays, CD, and fluorescence spectroscopy. Furthermore, the interaction between APOE isoforms and LPS was further substantiated through atomic resolution molecular dynamics simulations. The presence of LPS induced the aggregation of APOE isoforms, a phenomenon confirmed through specific amyloid staining, as well as fluorescence and electron microscopy. The scavenging effects of APOE3/4 isoforms were studied through both in vitro and in vivo experiments. In summary, our study established that APOE isoforms exhibit binding to LPS, with a more pronounced affinity and complex formation observed for APOE4 compared with APOE3. Furthermore, our data suggest that APOE isoforms neutralize LPS through aggregation, leading to a reduction of local inflammation in experimental animal models. In addition, both isoforms demonstrated inhibitory effects on the growth of P. aeruginosa and E. coli. These findings provide new insights into the multifunctionality of APOE in the human body, particularly its role in innate immunity during bacterial infections.
- MeSH
- apolipoprotein E3 * metabolismus chemie farmakologie MeSH
- apolipoprotein E4 * metabolismus chemie farmakologie MeSH
- Escherichia coli metabolismus MeSH
- lidé MeSH
- lipopolysacharidy * metabolismus chemie MeSH
- myši MeSH
- protein - isoformy chemie metabolismus MeSH
- Pseudomonas aeruginosa metabolismus MeSH
- simulace molekulární dynamiky MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- apolipoproteiny E genetika metabolismus MeSH
- arteriae carotides MeSH
- ateroskleróza genetika metabolismus patologie MeSH
- dospělí MeSH
- hyperlipoproteinemie genetika metabolismus MeSH
- lidé MeSH
- polymorfismus genetický MeSH
- průchodnost cév MeSH
- ultrasonografie dopplerovská metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
