| 1. |
- Hemdan, Tammer, et al.
(author)
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Stathmin-1 is a promising prognostic factor and potential therapeutic target in urinary bladder cancer
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Other publication (other academic/artistic)abstract
- Aim: The oncoprotein 18/stathmin 1 (STMN1), involved in cell cycle progression and cell migration, has been reported to be expressed in several types of cancer, and is associated with clinical outcome in e.g. breast and liver cancer. The aims in this study were to investigate the clinical significance of STMN1 and to examine if STMN1 might be a possible therapeutic target in urinary bladder cancer.Experimental design: Immunohistochemical analyses of STMN1 protein expression were performed in a wide-range tissue microarray (115 Ta-, 115 T1-, 112 T2-4-tumors) and in a metastatic primary tumor/matched metastasis-material (90 patients). In the T24 cell line, the effect of STMN1 on cell proliferation was evaluated by inhibiting the cellular expression of STMN using STMN1-siRNA.Results: Patients with T1- or muscle-invasive disease exhibiting high expression of the STMN1 protein had a poorer overall survival (OS) and disease specific survival (DSS). In a multivariate analysis adjusting for stage, age and gender the results were for T2-T4 patients: OS (HR=1.77 95% CI 1.02-3.07; p=0.04) and DSS (HR=2.04 95% CI 1.13-3.68; p=0.02); for T1-4 patients: DSS (HR=1.83 95% CI 1.09-3.08; p=0.02). In the metastatic bladder cancer material, the majority of the patients with one metastasis (69%) and with several matched metastases (70%) were STMN1-positive in both the primary tumor and the matched metastases. Moreover, the ability of the urinary bladder cancer cell line to grow was significantly reduced after 72 hours (p<0.0001) when transfecting the cells with a siRNA targeting STMN1.Conclusion: Our results suggest that STMN1 protein-expression has a potential both as a prognostic marker and a novel treatment target in urinary bladder cancer.
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| 2. |
- Heras, Gabriel, et al.
(author)
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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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In: Journal of Molecular Cell Biology. - : Oxford University Press (OUP). - 1674-2788 .- 1759-4685. ; 11:5, s. 356-370
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Journal article (peer-reviewed)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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| 3. |
- Namuduri, Arvind Venkat, et al.
(author)
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A Proteomic Approach to Identify Alterations in the Small Ubiquitin-like Modifier (SUMO) Network during Controlled Mechanical Ventilation in Rat Diaphragm Muscle
- 2017
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In: Molecular & Cellular Proteomics. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 1535-9476 .- 1535-9484. ; 16:6, s. 1081-1097
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Journal article (peer-reviewed)abstract
- The small ubiquitin-like modifier (SUMO) is as a regulator of many cellular functions by reversible conjugation to a broad number of substrates. Under endogenous or exogenous perturbations, the SUMO network becomes a fine sensor of stress conditions by alterations in the expression level of SUMO enzymes and consequently changing the status of SUMOylated proteins. The diaphragm is the major inspiratory muscle, which is continuously active under physiological conditions, but its structure and function is severely affected when passively displaced for long extents during mechanical ventilation (MV). An iatrogenic condition called Ventilator-Induced Diaphragm Dysfunction (VIDD) is a major cause of failure to wean patients from ventilator support but the molecular mechanisms underlying this dysfunction are not fully understood. Using a unique experimental Intensive Care Unit (ICU) rat model allowing long-term MV, diaphragm muscles were collected in rats control and exposed to controlled MV (CMV) for durations varying between 1 and 10 days. Endogenous SUMOylated diaphragm proteins were identified by mass spectrometry and validated with in vitro SUMOylation systems. Contractile, calcium regulator and mitochondrial proteins were of specific interest due to their putative involvement in VIDD. Differences were observed in the abundance of SUMOylated proteins between glycolytic and oxidative muscle fibers in control animals and high levels of SUMOylated proteins were present in all fibers during CMV. Finally, previously reported VIDD biomarkers and therapeutic targets were also identified in our datasets which may play an important role in response to muscle weakness seen in ICU patients. Data are available via ProteomeXchange with identifier PXD006085.
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| 4. |
- Namuduri, Arvind Venkat
(author)
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The role of SUMO pathway in pathophsiology of skeletal muscle
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Skeletal muscles are highly evolved and essential organs comprising 40 % of the total human body weight. They are essential in maintaining posture, energy metabolism, secrete hormones and act as central reserves for amino acids. Despite many studies on muscle physiology, there is a lack of understanding in cellular and molecular mechanisms leading to muscle adaptation, regeneration and progression of muscular disorders. Post-translational modifications (PTMs) markedly regulate the quality and the functionality of proteins in eukaryotic cells. One such PTM is the reversible conjugation of a 12 kDa moiety called Small Ubiquitin-like Modifier, SUMO, onto targeted proteins in a process termed SUMOylation. Alterations in expression or activity of SUMO conjugating/de-conjugating enzymes in association with genetic point mutations in the SUMO consensus sequence of specific targets have been implicated in conditions like cancer, diabetes, brain ischaemia, and cardiomyopathies. Given to the reversible and rapid dynamic response to detect alterations in physiological conditions, SUMO pathway is being extensively studied as a potential therapeutic target for some conditions of brain and cardiac muscle protection from diseases. Our interests are to translate the significance of the SUMO pathway to skeletal muscle health, investigate its modulation as consequence of adaptation to new muscle activities and study disturbances in the SUMO reaction that alter the SUMO conjugation on specific target proteins which are associated to skeletal muscle diseases. Ventilator Induced Diaphragm Dysfunction (VIDD) is a condition characterized by muscle dysfunction that occurs as side effect of Mechanical Ventilation. In diaphragms isolated from rats exposed to Controlled Mechanical ventilated (CMV), we observed significant changes in the overall SUMO muscle proteins due to alteration in the abundance of SUMO enzymes transcripts resulting in determining a new subset of SUMO targets. We studied the beneficial use of the drug BGP-15 administrated during CMV treatment that recovered the muscle contractile function partially due to a reorganization of the SUMO reaction. We further identified and characterized some specific skeletal muscle proteins targeted by the SUMO, which are associated with particular muscle functions. Mainly, we focused the attention on the E3 muscle ubiquitin ligase, MuRF1. We described the specific SUMO target site, enzymes involved in the SUMO reaction and the consequence of this PTM related to the properties of this protein. This discovery will open new avenues to understand the multiple functions of MuRF1 in muscle physiology and contribute to better understanding of muscular disorders that result from deregulation of MuRF1 activities mediated by SUMO conjugation. Finally, we provided an important facet to the differences in abundance of SUMO enzyme transcripts that we found across the different skeletal muscles to control their specific role along the body position. In conclusion, we also provided strong evidence of how the SUMO cycle may also be used as a cellular pathway target for new treatments for various skeletal muscle diseases.
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| 5. |
- Salah, Heba, et al.
(author)
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The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
- 2016
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:350
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Journal article (peer-reviewed)abstract
- Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by post-translational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.
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