| 1. |
- Appelqvist, Hanna, et al.
(författare)
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The lysosome: from waste bag to potential therapeutic target
- 2013
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Ingår i: Journal of Molecular Cell Biology. - : Oxford University Press (OUP): Policy B - Oxford Open Option D. - 1674-2788 .- 1759-4685. ; 5:4, s. 214-226
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Forskningsöversikt (refereegranskat)abstract
- Lysosomes are ubiquitous membrane-bound intracellular organelles with an acidic interior. They are central for degradation and recycling of macromolecules delivered by endocytosis, phagocytosis, and autophagy. In contrast to the rather simplified view of lysosomes as waste bags, nowadays lysosomes are recognized as advanced organelles involved in many cellular processes and are considered crucial regulators of cell homeostasis. The function of lysosomes is critically dependent on soluble lysosomal hydrolases (e.g. cathepsins) as well as lysosomal membrane proteins (e.g. lysosome-associated membrane proteins). This review focuses on lysosomal involvement in digestion of intra- and extracellular material, plasma membrane repair, cholesterol homeostasis, and cell death. Regulation of lysosomal biogenesis and function via the transcription factor EB (TFEB) will also be discussed. In addition, lysosomal contribution to diseases, including lysosomal storage disorders, neurodegenerative disorders, cancer, and cardiovascular diseases, is presented.
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| 2. |
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| 3. |
- Asp, Julia, 1973, et al.
(författare)
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Cardiomyocyte clusters derived from human embryonic stem cells share similarities with human heart tissue.
- 2010
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Ingår i: Journal of molecular cell biology. - : Oxford University Press (OUP). - 1759-4685 .- 1674-2788. ; 2:5, s. 276-83
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Tidskriftsartikel (refereegranskat)abstract
- Cardiotoxicity testing is a key activity in the pharmaceutical industry in order to detect detrimental effects of new drugs. A reliable human in vitro model would both be beneficial in selection of lead compounds and be important for reducing animal experimentation. However, the human heart is a complex organ composed of many distinct types of cardiomyocytes, but cardiomyocyte clusters (CMCs) derived from human embryonic stem cells could be an option for a cellular model. Data on functional properties of CMCs demonstrate similarities to their in vivo analogues in human. However, development of an in vitro model requires a more thorough comparison of CMCs to human heart tissue. Therefore, we directly compared individually isolated CMCs to human fetal, neonatal, adult atrial and ventricular heart tissues. Real-time qPCR analysis of mRNA levels and protein staining of ion channels and cardiac markers showed in general a similar expression pattern in CMCs and human heart. Moreover, a significant decrease in beat frequency was noted after addition of Zatebradine, a blocker to I(f) involved in regulation of spontaneous contraction in CMCs. The results underscore the similarities of CMCs to human cardiac tissue, and further support establishment of novel cardiotoxicity assays based on the CMCs in drug discovery.
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| 5. |
- Heras, Gabriel, et al.
(författare)
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Muscle RING-finger protein-1 (MuRF1) functions and cellular localization are regulated by SUMO1 post-translational modification
- 2019
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Ingår i: Journal of Molecular Cell Biology. - : Oxford University Press (OUP). - 1674-2788 .- 1759-4685. ; 11:5, s. 356-370
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Tidskriftsartikel (refereegranskat)abstract
- The muscle RING-finger protein-1 (MuRF1) is an E3 ubiquitin ligase expressed in skeletal and cardiac muscle tissues and it plays important roles in muscle remodeling. Upregulation of MuRF1 gene transcription participates in skeletal muscle atrophy, on contrary downregulation of protein expression leads to cardiac hypertrophy. MuRF1 gene point mutations have been found to generate protein aggregate myopathies defined as muscle disorder characterized by protein accumulation in muscle fibers. We have discovered that MuRF1 turned out to be also a target for a new post-translational modification arbitrated by conjugation of SUMO1 and it is mediated by the SUMO ligases E2 UBC9 and the E3 PIASγ/4. SUMOylation takes place at lysine 238 localized at the second coiled-coil protein domain that is required for efficient substrate interaction for polyubiquitination. We provided evidence that SUMOylation is essential for MuRF1 nuclear translocation and its mitochondria accumulation is enhanced in hyperglycemic conditions delivering a stabilization of the overall SUMOylated proteins in cultured myocytes. Thus, our findings add this SUMO1 post-translational modification as a new concept to understand muscle disorders related to the defect in MuRF1 activity.
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| 6. |
- Johansson, Ann-Sofie, et al.
(författare)
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Structure-activity relationships and thermal stability of human glutathione transferase P1-1 governed by the H-site residue 105
- 1998
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Ingår i: Journal of Molecular Cell Biology. - : Elsevier BV. - 1674-2788 .- 1759-4685 .- 0022-2836. ; 278:3, s. 687-698
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Tidskriftsartikel (refereegranskat)abstract
- Human glutathione transferase P1-1 (GSTP1-1) is polymorphic in amino acid residue 105, positioned in the substrate binding H-site. To elucidate the role of this residue an extensive characterization of GSTP1-1/Ile105 and GSTP1-1/Val105 was performed. Mutant enzymes with altered volume and hydrophobicity of residue 105, GSTP1-1/Ala105 and GSTP1-1/Trp105, were constructed and included in the study. Steady-state kinetic parameters and specific activities were determined using a panel of electrophilic substrates, with the aim of covering different types of reaction mechanisms. Analysis of the steady-state kinetic parameters indicates that the effect of the substitution of the amino acid in position 105 is highly dependent on substrate used. When 1-chloro-2,4-dinitrobenzene was used as substrate a change in the side-chain of residue 105 seemed primarily to cause changes in the KM value, while the kcat value was not distinctively affected. With other substrates, such as 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole and ethacrynic acid both kcat and KM values were altered by the substitution of amino acid 105. The constant for formation of the sigma-complex between 1,3, 5-trinitrobenzene and glutathione was shown to be dependent upon the volume of the amino acid in position 105. The nature of the amino acid in position 105 was also shown to affect the thermal stability of the enzyme at 50 degrees C, indicating an important role for this residue in the stabilization of the enzyme. The GSTP1-1/Ile105 variant was approximately two to three times more stable than the Val105 variant as judged by their half-lives. The presence of glutathione in the incubation buffer afforded a threefold increase in the half-lives of the enzymes. Thus, the thermal stability of the enzyme and depending on substrate, both KM values and turnover numbers are influenced by substitutions in position 105 of GSTP1-1.
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| 7. |
- Karakostis, Konstantinos, et al.
(författare)
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A single synonymous mutation determines the phosphorylation and stability of the nascent protein
- 2019
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Ingår i: Journal of Molecular Cell Biology. - : Oxford University Press. - 1674-2788 .- 1759-4685. ; 11:3, s. 187-199
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Tidskriftsartikel (refereegranskat)abstract
- p53 is an intrinsically disordered protein with a large number of post-translational modifications and interacting partners. The hierarchical order and subcellular location of these events are still poorly understood. The activation of p53 during the DNA damage response (DDR) requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53. This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis. Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53. A single synonymous mutation in p53 codon 22 (L22L) prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress. The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2, which requires its interaction with the ribosomal proteins RPL5 and RPL11. These results show how the ATM kinase phosphorylates the p53 protein while it is being synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein.
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| 10. |
- Schwartz, Yuri B, et al.
(författare)
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A little bit of sugar makes polycomb better
- 2009
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Ingår i: Journal of molecular cell biology. - : Oxford University Press (OUP). - 1759-4685 .- 1674-2788. ; 1:1, s. 11-12
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptional repression by Polycomb group (PcG) proteins is now sweetened by the discovery of the essential role of O-GlcNAc glycosylation in the process. PcG protein polyhomeotic may be the key target, but alternative or additional functions including repression of transcription through glycosylation of the C-terminal domain of RNA polymerase II are also possible.
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