scholarly journals Menin Missense Mutants Encoded by the MEN1 Gene that Are Targeted to the Proteasome: Restoration of Expression and Activity by CHIP siRNA

2012 ◽  
Vol 97 (2) ◽  
pp. E282-E291 ◽  
Author(s):  
Lucie Canaff ◽  
Jean-François Vanbellinghen ◽  
Ippei Kanazawa ◽  
Hayeon Kwak ◽  
Natasha Garfield ◽  
...  
Keyword(s):  
Small Interfering Rna ◽  
Target Genes ◽  
Kinase Inhibitors ◽  
Proteasome Inhibitors ◽  
Expression Vectors ◽  
Missense Mutations ◽  
Interacting Protein ◽  
Men1 Gene ◽  
Interfering Rna ◽  
Expression And Activity

Context: In multiple endocrine neoplasia type 1 (MEN1) characterized by tumors of parathyroid, enteropancreas, and anterior pituitary, missense mutations in the MEN1 gene product, menin, occur in a subset of cases. The mutant proteins are degraded by the proteasome. However, whether their expression and activity can be restored is not known. Objective: Our objective was to functionally characterize a panel of 16 menin missense mutants, including W423R and S443Y identified in new MEN1 families, with respect to protein stability, targeting to the proteasome and restoration of expression by proteasome inhibitors and expression and function by small interfering RNA technology. Methods: Flag-tagged wild-type (WT) and missense menin mutant expression vectors were transiently transfected in human embryonic kidney (HEK293) and/or rat insulinoma (Rin-5F) cells. Results: The majority of mutants were short-lived, whereas WT menin was stable. Proteasome inhibitors MG132 and PS-341 and inhibition of the chaperone, heat-shock protein 70 (Hsp70), or the ubiquitin ligase, COOH terminus of Hsp70-interacting protein (CHIP), by specific small interfering RNA, restored the levels of the mutants, whereas that of WT menin was largely unaffected. Inhibition of CHIP restored the ability of mutants to mediate normal functions of menin: TGF-β up-regulation of the promoters of its target genes, the cyclin-dependent kinase inhibitors p15 and p21 as well as TGF-β inhibition of cell numbers. Conclusion: When the levels of missense menin mutants that are targeted to the proteasome are normalized they may function similarly to WT menin. Potentially, targeting specific components of the proteasome chaperone pathway could be beneficial in treating a subset of MEN1 cases.

scholarly journals A small interfering RNA (siRNA) database for SARS-CoV-2

2020 ◽  
Author(s):  
Inácio Gomes Medeiros ◽  
André Salim Khayat ◽  
Beatriz Stransky ◽  
Sidney Emanuel Batista dos Santos ◽  
Paulo Pimentel de Assumpção ◽  
...  
Keyword(s):  
Human Genome ◽  
Design Process ◽  
Small Interfering Rna ◽  
Target Genes ◽  
Information Base ◽  
Global Pandemic ◽  
The World ◽  
Rna Genome ◽  
Target Sequences ◽  
Interfering Rna

ABSTRACTCoronavirus disease 2019 (COVID-19) rapidly transformed into a global pandemic, for which a demand for developing antivirals capable of targeting the SARS-CoV-2 RNA genome and blocking the activity of its genes has emerged. In this work, we propose a database of SARS-CoV-2 targets for siRNA approaches, aiming to speed the design process by providing a broad set of possible targets and siRNA sequences. Beyond target sequences, it also displays more than 170 features, including thermodynamic information, base context, target genes and alignment information of sequences against the human genome, and diverse SARS-CoV-2 strains, to assess whether siRNAs targets bind or not off-target sequences. This dataset is available as a set of four tables in a single spreadsheet file, each table corresponding to sequences of 18, 19, 20, and 21 nucleotides length, respectively, aiming to meet the diversity of technology and expertise among labs around the world concerning siRNAs design of varied sizes, more specifically between 18 and 21nt length. We hope that this database helps to speed the development of new target antivirals for SARS-CoV-2, contributing to more rapid and effective responses to the COVID-19 pandemic.

Small interfering RNA (siRNA) to target genes and molecular pathways in glioblastoma therapy: Current status with an emphasis on delivery systems

Life Sciences ◽  
2021 ◽  
pp. 119368
Author(s):  
Sepideh Mirzaei ◽  
Mahmood Khaksary Mahabady ◽  
Amirhossein Zabolian ◽  
Alireza Abbaspour ◽  
Peyman Fallahzadeh ◽  
...  
Keyword(s):  
Small Interfering Rna ◽  
Target Genes ◽  
Delivery Systems ◽  
Current Status ◽  
Molecular Pathways ◽  
Interfering Rna

scholarly journals Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis

2012 ◽  
Vol 71 (5) ◽  
pp. 785-789 ◽  
Author(s):  
Angelika Horn ◽  
Trayana Kireva ◽  
Katrin Palumbo-Zerr ◽  
Clara Dees ◽  
Michal Tomcik ◽  
...  
Keyword(s):  
Small Interfering Rna ◽  
Target Genes ◽  
Hedgehog Signalling ◽  
Dermal Fibrosis ◽  
Tight Skin ◽  
Gli Transcription Factors ◽  
Interfering Rna ◽  
Therapeutic Settings ◽  
Dermal Thickening ◽  
Activation Status

ObjectivesTissue fibrosis is a leading cause of death in patients with systemic sclerosis (SSc). Effective antifibrotic treatments are not available. Here, the authors investigated inhibition of hedgehog signalling by targeting Smoothened (Smo) as a novel antifibrotic approach.MethodsThe activation status of the hedgehog pathway was assessed by immunohistochemistry for Gli transcription factors and by quantification of hedgehog target genes. Hedgehog signalling was inhibited by the selective inhibitor LDE223 and by small interfering RNA against Smo in the models of bleomycin-induced dermal fibrosis and in tight-skin-1 mice.ResultsHedgehog signalling is activated in SSc and in murine models of SSc. Inhibition of Smo either by LDE223 or by small interfering RNA prevented dermal thickening, myofibroblast differentiation and accumulation of collagen upon challenge with bleomycin. Targeting Smo also exerted potent antifibrotic effects in tight-skin-1 mice and did prevent progression of fibrosis and induced regression of pre-established fibrosis.ConclusionsInhibition of hedgehog signalling exerted potent antifibrotic effects in preclinical models of SSc in both preventive and therapeutic settings. These findings might have direct translational implications because inhibitors of Smo are already available and yielded promising results in initial clinical trials.

Proinflammatory treatment of astrocytes with lipopolysaccharide results in augmented Ca2+ signaling through increased expression of VIA phospholipase A2 (iPLA2)

2011 ◽  
Vol 300 (3) ◽  
pp. C542-C549 ◽  
Author(s):  
Mikhail Strokin ◽  
Marina Sergeeva ◽  
Georg Reiser
Keyword(s):  
Endoplasmic Reticulum ◽  
Small Interfering Rna ◽  
Signal Transmission ◽  
Brain Inflammation ◽  
Inflammatory Conditions ◽  
Bromoenol Lactone ◽  
Interfering Rna ◽  
The Brain ◽  
Expression And Activity

Many Ca2+-regulated intracellular processes are involved in the development of neuroinflammation. However, the changes of Ca2+ signaling in the brain under inflammatory conditions were hardly studied. ATP-induced Ca2+ signaling is a central event of signal transmission in astrocytic networks. We investigated primary astrocytes after proinflammatory stimulation with lipopolysaccharide (LPS; 100 ng/ml) for 6–24 h. We reveal that Ca2+ responses to purinergic ATP stimulation are significantly increased in amplitude and duration after stimulation with LPS. We detected that increased amplitudes of Ca2+ responses to ATP in LPS-treated astrocytes can be explained by substantial increase of Ca2+ load in stores in endoplasmic reticulum. The mechanism implies enhanced Ca2+ store refilling due to the amplification of capacitative Ca2+ entry. The reason for the increased duration of Ca2+ responses in LPS-treated cells is also the amplified capacitative Ca2+ entry. Next, we established that the molecular mechanism for the LPS-induced amplification of Ca2+ responses in astrocytes is increased expression and activity of VIA phospholipase A2 (VIA iPLA2). Indeed, both gene silencing with specific small interfering RNA and pharmacological inhibition of VIA iPLA2 with S-bromoenol lactone reduced the load of the Ca2+ stores and caused a decrease in the amplitudes of Ca2+ responses in LPS-treated astrocytes to values, which were comparable with those in untreated cells. Our findings highlight a novel regulatory role of VIA iPLA2 in development of inflammation in brain. We suggest that this enzyme might be a possible target for treatment of pathologies related to brain inflammation.

scholarly journals ERK1c regulates Golgi fragmentation during mitosis

2006 ◽  
Vol 172 (6) ◽  
pp. 885-897 ◽  
Author(s):  
Yoav D. Shaul ◽  
Rony Seger
Keyword(s):  
Small Interfering Rna ◽  
Cell Cycle Regulation ◽  
Mitotic Progression ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Alternatively Spliced ◽  
Golgi Fragmentation ◽  
Cycle Regulation ◽  
Interfering Rna ◽  
Expression And Activity

Extracellular signal-regulated kinase 1c (ERK1c) is an alternatively spliced form of ERK1 that is regulated differently than other ERK isoforms. We studied the Golgi functions of ERK1c and found that it plays a role in MEK-induced mitotic Golgi fragmentation. Thus, in late G2 and mitosis of synchronized cells, the expression and activity of ERK1c was increased and it colocalized mainly with Golgi markers. Small interfering RNA of ERK1c significantly attenuated, whereas ERK1c overexpression facilitated, mitotic Golgi fragmentation. These effects were also reflected in mitotic progression, indicating that ERK1c is involved in cell cycle regulation via modulation of Golgi fragmentation. Although ERK1 was activated in mitosis as well, it could not replace ERK1c in regulating Golgi fragmentation. Therefore, MEKs regulate mitosis via all three ERK isoforms, where ERK1c acts specifically in the Golgi, whereas ERK1 and 2 regulate other mitosis-related processes. Thus, ERK1c extends the specificity of the Ras-MEK cascade by activating ERK1/2-independent processes.

scholarly journals Nanomedical Devices and Cancer Theranostics

2020 ◽  
Vol 6 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Mohamed Moumaris ◽  
Jean-Michel Bretagne ◽  
Nisen Abuaf
Keyword(s):  
Quantum Dot ◽  
Small Interfering Rna ◽  
Target Genes ◽  
Malignant Tumors ◽  
Whole Body ◽  
Systemic Delivery ◽  
Non Invasive ◽  
Current Therapies ◽  
Cancer Theranostics ◽  
Interfering Rna

The current therapies against cancer showed limited success. Nanotechnology is a promising strategy for cancer tracking, diagnosis, and therapy. The hybrid nanotechnology assembled several materials in a multimodal system to develop multifunctional approaches to cancer treatment. The quantum dot and polymer are some of these hybrid nanoparticle platforms. The quantum dot hybrid system possesses photonic and magnetic properties, allowing photothermal therapy and live multimodal imaging of cancer. These quantum dots were used to convey medicines to cancer cells. Hybrid polymer nanoparticles were utilized for the systemic delivery of small interfering RNA to malignant tumors and metastasis. They allowed non-invasive imaging to track in real-time the biodistribution of small interfering RNA in the whole body. They offer an opportunity to treat cancers by specifically silencing target genes. This review highlights the major nanotechnology approaches to effectively treat cancer and metastasis.

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