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Blog of Signaling Pathways

Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration

827 views | Apr 19 2018

Aras S et al. showed that binding of MNRR1 to COX is promoted by phosphorylation at tyrosine-99 and that this interaction stimulates respiration. We show that phosphorylation of MNRR1 takes place in mitochondria and is mediated by Abl2 kinase (ARG). A family with Charcot-Marie-Tooth disease type 1A with an exaggerated phenotype harbors a Q112H mutation in MNRR1, located in a domain that is necessary for transcriptional activation by MNRR1. Furthermore, the mutation causes the protein to function suboptimally in the mitochondria in response to cellular stress. The Q112H mutation hinders the ability of the protein to interact with Abl kinase, leading to defective tyrosine phosphorylation and a resultant defect in respiration. [Read the Full Post]

Evaluation of cardioprotective effect of aqueous extract of Garcinia indica Linn. fruit rinds on isoprenaline-induced myocardial injury in Wistar albino rats

681 views | Apr 18 2018

Patel KJ et al. found that the aqueous extract of G. indica was not found to be cardioprotective against myocardial injury. [Read the Full Post]

P53-dependent upregulation of neutral sphingomyelinase-2: role in doxorubicin-induced growth arrest

533 views | Apr 18 2018

Shamseddine AA et al. identifyd nSMase2 as a novel p53 target gene, regulated by the DNA damage pathway to induce cell growth arrest. [Read the Full Post]

Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment

371 views | Apr 17 2018

Chaudhari U et al. revealed early expression signatures of genes involved in formation of sarcomeric structures, regulation of ion homeostasis and induction of apoptosis. Eighty-four significantly deregulated genes related to cardiac functions, stress and apoptosis were validated using real-time PCR. The expression of the 84 genes was further studied by real-time PCR in hiPSC-CMs incubated with daunorubicin and mitoxantrone, further anthracycline family members that are also known to induce cardiotoxicity. A panel of 35 genes was deregulated by all three anthracycline family members and can therefore be expected to predict the cardiotoxicity of compounds acting by similar mechanisms as doxorubicin, daunorubicin or mitoxantrone. The identified gene panel can be applied in the safety assessment of novel drug candidates as well as available therapeutics to identify compounds that may cause cardiotoxicity. [Read the Full Post]

CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours

358 views | Apr 17 2018

Costa-Cabral S et al. suggested that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation. [Read the Full Post]

Mdivi-1 Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats, Possibly via Inhibition of Drp1-Activated Mitochondrial Fission and Oxidative Stress

356 views | Apr 16 2018

Wu P et al. suggested that Mdivi-1 exerts neuroprotective effects against cell death induced by SAH and the underlying mechanism may be inhibition of Drp1-activated mitochondrial fission and oxidative stress. [Read the Full Post]

Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455

864 views | Apr 16 2018

Wu D et al. revealed that the interactions of LY2874455 to FGFR4 are largely conserved in 4 FGFRs, explaining at least partly, the broad inhibitory activity of LY2874455 toward 4 FGFRs. Consequently, our studies reveal new insights into the pan-FGFR selectivity of LY2874455 and provide a structural basis for developing novel FGFR inhibitors that target FGFR1-4 broadly. [Read the Full Post]

Proliferation Markers Are Associated with MET Expression in Hepatocellular Carcinoma and Predict Tivantinib Sensitivity In Vitro

0 views | Apr 15 2018

Rebouissou S et al. indicated that tivantinib acts as an antimitotic compound, and cell proliferation markers are the best predictors of its antitumor efficacy in cell lines. Ki67 expression should be tested in clinical trials to predict tivantinib response. [Read the Full Post]

Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels

385 views | Apr 15 2018

Li GB, et al. describe the mechanism by which PINK1 contributes to polyphyllin I-induced mitophagy and apoptosis and suggest that polyphyllin I may be an effective drug for breast cancer treatment. [Read the Full Post]

Inhibition of autophagy enhances effects of PF-04691502 on apoptosis and DNA damage of lung cancer cells

1686 views | Apr 14 2018

Fei HR et al. suggested that a strategy of blocking autophagy to enhance the activity of PI3K/mTOR inhibitors warrants further attention in treatment of NSCLC cells. [Read the Full Post]

COPS5 amplification and overexpression confers tamoxifen-resistance in ERα-positive breast cancer by degradation of NCoR

1461 views | Apr 14 2018

Lu R et al. demonstrated that genetic inhibition of the isopeptidase activity of COPS5 is sufficient to re-sensitize the resistant breast cancer cells to tamoxifen-treatment, offering a potential therapeutic approach for endocrine-resistant breast cancer patients. [Read the Full Post]

Evodiamine inhibits PDGF‑BB‑induced proliferation of rat vascular smooth muscle cells through the suppression of cell cycle progression and oxidative stress

1097 views | Apr 13 2018

Ge X et al. provided important insights into the mechanisms underlying the vasoprotective actions of evodiamine and suggested that it may be a useful therapeutic agent for the treatment of vascular occlusive disease. [Read the Full Post]

The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling

368 views | Apr 12 2018

Qiu J et al. demonstrated that SINO exerts a neuroprotective effect in ischemic stroke by inhibiting NLRP3 inflammasomes via the AMPK pathway, which also provides evidence of a novel treatment for clinical stroke therapy. [Read the Full Post]

Tanshinone I inhibits tumor angiogenesis by reducing Stat3 phosphorylation at Tyr705 and hypoxia-induced HIF-1α accumulation in both endothelial and tumor cells

379 views | Apr 12 2018

Wang Y et al. revealed unique characteristics of tanshinone-1 and its improved derivatives as promising angiogenesis inhibitors. [Read the Full Post]

Synergistic effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway or NUP214-ABL1 fusion protein in human Acute Lymphoblastic Leukemia

0 views | Apr 11 2018

Simioni C et al. indicated that either single or combined administration of drugs against the different targets displayed inhibition of cellular viability associated with a concentration-dependent induction of apoptosis, cell cycle arrest in G0/G1 phase and autophagy, having the combined treatments a significant synergistic cytotoxic effect. Co-targeting NUP214-ABL1 fusion gene and PI3K/Akt/mTOR signaling pathway could represent a new and effective pharmacological strategy to improve the outcome in NUP214-ABL1 positive T-ALL. [Read the Full Post]

The HER2 inhibitor TAK165 Sensitizes Human Acute Myeloid Leukemia Cells to Retinoic Acid-Induced Myeloid Differentiation by activating MEK/ERK mediated RARα/STAT1 axis

1191 views | Apr 11 2018

Shao X et al. indicated that our study is the first to evaluate the synergy of TAK165 and ATRA in AML cell differentiation and to assess new opportunities for the combination of TAK165 and ATRA as a promising approach for future differentiation therapy. [Read the Full Post]

Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area

716 views | Apr 10 2018

Dutton JW 3rd et al. supported the possibility that ALK might be a novel target of pharmacotherapy for reducing excessive alcohol consumption. [Read the Full Post]

FcγRIIB-Independent Mechanisms Controlling Membrane Localization of the Inhibitory Phosphatase SHIP in Human B Cells

1366 views | Apr 10 2018

Pauls SD et al. indicated that FcγRIIB is not uniquely able to promote membrane recruitment of SHIP, but rather modulates its function via formation of distinct signaling complexes. Membrane recruitment of SHIP via Syk-dependent mechanisms may be an important factor modulating immunoreceptor signaling. [Read the Full Post]

Susceptibility of porcine endogenous retrovirus to anti-retroviral inhibitors

376 views | Apr 09 2018

Argaw T et al. indicated that some of the licensed anti-retroviral drugs may be useful for controlling PERV infection. However, the efficacy at nanomolar concentrations put forward integrase inhibitors as a drug that has the potential to be useful in the event that xenotransplantation recipients have evidence of PERV transmission and replication. [Read the Full Post]

Novel Akt activator SC-79 is a potential treatment for alcohol-induced osteonecrosis of the femoral head

1108 views | Apr 09 2018

Chen YX et al. showed that alcohol-induced ONFH is associated with suppression of p-Akt-Ser473 in the Akt/GSK3β/β-catenin signaling pathway in bone mesenchymal stem cells. We propose that SC-79 treatment to rescue Akt activation could be tested in the clinic as a potential therapeutic approach to preventing the development of alcohol-induced ONFH. [Read the Full Post]