scholarly journals Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT 2A neuropathy

EMBO Reports ◽  
2018 ◽  
Vol 19 (8) ◽  
Author(s):  
Najla El Fissi ◽  
Manuel Rojo ◽  
Aїcha Aouane ◽  
Esra Karatas ◽  
Gabriela Poliacikova ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Gain And Loss ◽  
Drosophila Models

scholarly journals Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT 2A neuropathy

EMBO Reports ◽  
2020 ◽  
Vol 21 (7) ◽  
Author(s):  
Najla El Fissi ◽  
Manuel Rojo ◽  
Aїcha Aouane ◽  
Esra Karatas ◽  
Gabriela Poliacikova ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Gain And Loss ◽  
Drosophila Models

scholarly journals Gain- and loss-of-function mutations inZat10enhance the tolerance of plants to abiotic stress

FEBS Letters ◽  
2006 ◽  
Vol 580 (28-29) ◽  
pp. 6537-6542 ◽  
Author(s):  
Ron Mittler ◽  
YongSig Kim ◽  
Luhua Song ◽  
Jesse Coutu ◽  
Alicia Coutu ◽  
...  
Keyword(s):  
Abiotic Stress ◽  
Loss Of Function ◽  
Gain And Loss

Abstract 1100: Gain and loss of function genome-wide CRISPR screens identify Hippo signaling as an important driver of resistance inEGFRmutant lung cancer

2021 ◽  
Author(s):  
Matthias Pfeifer ◽  
Jonathan S. Brammeld ◽  
Stacey Price ◽  
Matthew Martin ◽  
Hannah Thorpe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Hippo Signaling ◽  
Loss Of Function ◽  
Genome Wide ◽  
Gain And Loss

scholarly journals Gain and Loss of Function of P2X7 Receptors: Mechanisms, Pharmacology and Relevance to Diabetic Neuropathic Pain

2014 ◽  
Vol 10 ◽  
pp. 1744-8069-10-37 ◽  
Author(s):  
Daniel Ursu ◽  
Philip Ebert ◽  
Emily Langron ◽  
Cara Ruble ◽  
Leanne Munsie ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Loss Of Function ◽  
Diabetic Neuropathic Pain ◽  
P2x7 Receptors ◽  
Gain And Loss

Lin28B/Let-7 Axis Regulates Multiple Myeloma Proliferation By Enhancing c-Myc and Ras Survival Pathways

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 273-273
Author(s):  
Salomon Manier ◽  
John T Powers ◽  
Antonio Sacco ◽  
Michaela R Reagan ◽  
Michele Moschetta ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Advisory Board ◽  
Loss Of Function ◽  
Advisory Committees ◽  
Expression Levels ◽  
Gain And Loss

Abstract Background MicroRNAs (miRNAs) play a pivotal role in tumorigenesis, due to their ability to target mRNAs involved in the regulation of cell proliferation, survival and differentiation. Lin28B is an RNA binding protein that regulates Let-7 miRNA maturation. Lin28B and Let-7 have been described to act as oncogenes or tumor suppressor genes, respectively, as demonstrated both in solid cancer and hematologic malignancies. However, the role of the Lin28B/Let-7 axis in Multiple Myeloma (MM) has not been studied. Method Lin28B level expression in MM patients was studied using previously published gene expression profiling (GEP) datasets. Let-7 expression levels were assessed in CD138+ primary MM cells and bone marrow stromal cells (BMSCs) by using PCR, as well as in circulating exosomes using miRNA array (Nanostring® Technology). Exosomes were collected from both normal and MM peripheral blood, using ultracentrifugation; and further studied by using electron microscopy and immunogold labeling for the detection of CD63 and CD81. The knockdown of Lin28B was performed on MM cell lines (U266, MM.1S, MOLP-8) by using a lentiviral Lin28B shRNA. Gain- and loss-of function studies for Let-7 were performed using Let-7 mimic and anti-Let-7 transfection in MM cell lines (MM1S, U266) and primary BMSCs. Cell proliferation has been evaluated by using thymidine assays. Effects of Let-7 and Lin28B on signaling cascades have been evaluated by western blot. Results Two independent GEP datasets (GSE16558; GSE2658) were analyzed for Lin28B expression, showing a significantly higher level in MM patients compared to healthy controls. In addition, high Lin28B levels correlated with a shorter overall survival (p = 0.0226). We next found that the Let-7 family members are significantly down-regulated in MM primary cells, particularly Let-7a and b (5 fold change, p < 0.05), as demonstrated by using qRT-PCR. Similarly, miRNA arrays showed a lower expression of Let-7-related miRNAs in circulating exosomes obtained from MM patients compared to healthy individuals. We further dissected the functional relevance of Lin28B in MM cells, by performing Lin28 knockdown (KD) in MM cell lines (U266, MOLP-8). This led to a significant decrease in MM cell proliferation associated with G1 phase cell cycle arrest. This was supported by up-regulation of Let-7 and down-regulation of c-Myc, Ras and Cyclin D1 in Lin28 KD MM cells. To further prove that Lin28B-dependent effects on MM cells are mediated by Let7, we next showed that let-7 gain- and loss-of-function studies regulate MM cell proliferation and Myc expression. Lin28B regulation in MM cells is dependent on Let-7, as demonstrated by an increase of both cell proliferation and c-Myc expression after anti-Let-7 transfection in the Lin28B KD cells. We therefore studied the regulation of Let-7 in MM cells through the interaction with BMSCs. Let-7 expression levels were significantly lower in BMSCs obtained from MM patients compared to healthy donors. Interestingly, the Let-7 expression level in MM cells was increased after co-culture with Let-7 over-expressing BMSCs, associated with a decrease of both cell proliferation and c-Myc expression. This suggests a potential transfer of Let-7 from BMSCs to MM cells. Conclusion This work describes a new signaling pathway involving Lin28B, Let-7, Myc and Ras in MM. Let-7 expression in MM cells is also regulated through the interaction of MM cells with BMSCs, leading to cell proliferation and Myc regulation in MM. Interference with this pathway might offer therapeutic perspectives. Disclosures: Leleu: CELGENE: Honoraria; JANSSEN: Honoraria. Daley:Johnson and Johnson: Consultancy, Membership on an entity’s Board of Directors or advisory committees; MPM Capital: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity’s Board of Directors or advisory committees; iPierian: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Solasia, KK: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Ghobrial:Onyx: Advisoryboard Other; BMS: Advisory board, Advisory board Other, Research Funding; Noxxon: Research Funding; Sanofi: Research Funding.

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