scholarly journals Piezo1 activation using Yoda1 inhibits macropinocytosis and proliferation of cancer cells

2021 ◽  
Author(s):  
Masashi Kuriyama ◽  
Hisaaki Hirose ◽  
Toshihiro Masuda ◽  
Masachika Shudou ◽  
Jan Vincent V Arafiles ◽  
...  
Keyword(s):  
Cancer Cell Proliferation ◽  
Channel Activity ◽  
Membrane Deformation ◽  
Membrane Ruffling ◽  
Mechanosensitive Ion Channel ◽  
Epidermal Growth ◽  
Calcium Activated Potassium Channel ◽  
The Impact ◽  
Lamellipodia Formation ◽  
Actin Rearrangement

Macropinocytosis is a type of endocytosis accompanied by actin rearrangement-driven membrane deformation, such as lamellipodia formation and membrane ruffling, followed by macropinosome formation. A certain number of mammalian mechanosensors are sensitive to membrane deformation and tension. However, it remains unclear whether macropinocytosis is regulated by mechanosensors. Focusing on the mechanosensitive ion channel Piezo1, we found that Yoda1, a Piezo1 agonist, potently inhibits macropinocytosis induced by epidermal growth factor (EGF). Although studies with Piezo1 knockout cells suggest that Piezo1 itself is not physiologically indispensable for macropinocytosis regulation, Yoda1 inhibited ruffle formation depending on the extracellular Ca2+ influx through Piezo1 and on the activation of the calcium-activated potassium channel KCa3.1. This suggests that Ca2+ ions can regulate EGF-stimulated macropinocytosis. Moreover, Yoda1 impaired cancer cell proliferation, suggesting the impact of macropinocytosis inhibition. We propose the potential for cancer therapy by macropinocytosis inhibition through the regulation of a mechanosensitive channel activity.

scholarly journals Estrogen receptor alpha controls gene expression via translational offsetting

2018 ◽  
Author(s):  
Julie Lorent ◽  
Richard J. Rebello ◽  
Vincent van Hoef ◽  
Mitchell G. Lawrence ◽  
Krzysztof J. Szkop ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Mrna Translation ◽  
Translational Efficiency ◽  
Cancer Cell Proliferation ◽  
Altered Expression ◽  
Receptor Alpha ◽  
Protein Levels ◽  
Transcriptional Output ◽  
The Impact

AbstractEstrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNA and protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translational efficiency including structured 5’UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modification enzymes, whereas altered expression of U34-modification enzymes disrupts ERα dependent translational offsetting. Altogether, we unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs, and highlight that translational offsetting may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.

scholarly journals Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. 2437-2453
Author(s):  
Pauline E Schneeberger ◽  
Fanny Kortüm ◽  
Georg Christoph Korenke ◽  
Malik Alawi ◽  
René Santer ◽  
...  
Keyword(s):  
Nervous System ◽  
Autonomic Nervous System ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Developmental Delay ◽  
Autonomic Nervous ◽  
Organ Systems ◽  
Tnf Α ◽  
Epidermal Growth ◽  
The Impact

Abstract In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

BKCa channel activation by membrane-associated cGMP kinase may contribute to uterine quiescence in pregnancy

2000 ◽  
Vol 279 (6) ◽  
pp. C1751-C1759 ◽  
Author(s):  
Xiao-Bo Zhou ◽  
Ge-Xin Wang ◽  
Peter Ruth ◽  
Bernd Hüneke ◽  
Michael Korth
Keyword(s):  
Bkca Channel ◽  
Channel Activity ◽  
Inhibitory Peptide ◽  
Channel Activation ◽  
Myometrial Cells ◽  
Maximal Activation ◽  
Channel Expression ◽  
Membrane Bound ◽  
Calcium Activated Potassium Channel ◽  
Inside Out

We investigated the influence of pregnancy on large-conductance calcium-activated potassium channel (BKCa) activity ( NP o) and on channel expression in membranes of isolated human myometrial smooth muscle cells. NP o in inside-out patches was higher in pregnant myometria (PM) compared with nonpregnant myometria (NPM), and the half-maximal activation potential was shifted by 39 mV to more negative potentials. This effect was not due to an enhanced BKCachannel expression. In the presence of cAMP kinase (PKA) or cGMP kinase (PKG), NP o increased in patches from PM but decreased in those from NPM. Western blot analysis and use of a specific PKG inhibitor (1 μM KT-5823) verified the existence of a partially active membrane-associated PKG. Inhibition of PKA by 100 nM PKI, the inhibitory peptide of PKA, had no effect on NP o. 8- p-Chlorophenylthio-cGMP (8-pCPT-cGMP) hyperpolarized cells from PM. This effect was abolished by iberiotoxin, a specific blocker of BKCachannels. It is concluded that an endogenous, membrane-bound PKG in myometrial cells specifically enhances BKCa channel activity during pregnancy and thus may contribute to uterine quiescence during pregnancy.

scholarly journals Arabidopsis MSL10 Has a Regulated Cell Death Signaling Activity That Is Separable from Its Mechanosensitive Ion Channel Activity

2014 ◽  
Vol 26 (7) ◽  
pp. 3115-3131 ◽  
Author(s):  
Kira M. Veley ◽  
Grigory Maksaev ◽  
Elizabeth M. Frick ◽  
Emma January ◽  
Sarah C. Kloepper ◽  
...  
Keyword(s):  
Cell Death ◽  
Ion Channel ◽  
Channel Activity ◽  
Regulated Cell Death ◽  
Mechanosensitive Ion Channel ◽  
Cell Death Signaling ◽  
Signaling Activity

scholarly journals EGFRAmplification and Glioblastoma Stem-Like Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Katrin Liffers ◽  
Katrin Lamszus ◽  
Alexander Schulte
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Current Knowledge ◽  
Growth Factor Receptor ◽  
Model Systems ◽  
Preclinical Research ◽  
Epidermal Growth ◽  
Methodological Approaches ◽  
The Impact

Glioblastoma (GBM), the most common malignant brain tumor in adults, contains a subpopulation of cells with a stem-like phenotype (GS-cells). GS-cells can be maintainedin vitrousing serum-free medium supplemented with epidermal growth factor, basic fibroblast growth factor-2, and heparin. However, this method does not conserve amplification of the Epidermal Growth Factor Receptor (EGFR) gene, which is present in over 50% of all newly diagnosed GBM cases. GS-cells with retainedEGFRamplification could overcome the limitations of currentin vitromodel systems and contribute significantly to preclinical research on EGFR-targeted therapy. This review recapitulates recent methodological approaches to expand stem-like cells from GBM with differentEGFRstatus in order to maintain EGFR-dependent intratumoral heterogeneityin vitro. Further, it will summarize the current knowledge about the impact ofEGFRamplification and overexpression on the stem-like phenotype of GBM-derived GS-cells and different approaches to target the EGFR-dependent GS-cell compartment of GBM.

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