Search results for "MTO"

TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT.

2011

International audience; BACKGROUND: TRAIL/Apo2L is a pro-apoptotic ligand of the TNF family that engages the apoptotic machinery through two pro-apoptotic receptors, TRAIL-R1 and TRAIL-R2. This cell death program is tightly controlled by two antagonistic receptors, TRAIL-R3 and TRAIL-R4, both devoid of a functional death domain, an intracellular region of the receptor, required for the recruitment and the activation of initiator caspases. Upon TRAIL-binding, TRAIL-R4 forms a heteromeric complex with the agonistic receptor TRAIL-R2 leading to reduced caspase-8 activation and apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: We provide evidence that TRAIL-R4 can also exhibit, in a ligand independent…

Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast can…

2010

Introduction Accumulating evidence suggests that both levels and activity of the estrogen receptor (ER) and the progesterone receptor (PR) are dramatically influenced by growth-factor receptor (GFR) signaling pathways, and that this crosstalk is a major determinant of both breast cancer progression and response to therapy. The phosphatidylinositol 3-kinase (PI3K) pathway, a key mediator of GFR signaling, is one of the most altered pathways in breast cancer. We thus examined whether deregulated PI3K signaling in luminal ER+ breast tumors is associated with ER level and activity and intrinsic molecular subtype. Methods We defined two independent molecular signatures of the PI3K pathway: a pro…

Syntaxin13 expression is regulated by mammalian target of rapamycin (mTOR) in injured neurons to promote axon regeneration.

2014

Injured peripheral neurons successfully activate intrinsic signaling pathways to enable axon regeneration. We have previously shown that dorsal root ganglia (DRG) neurons activate the mammalian target of rapamycin (mTOR) pathway following injury and that this activity enhances their axon growth capacity. mTOR plays a critical role in protein synthesis, but the mTOR-dependent proteins enhancing the regenerative capacity of DRG neurons remain unknown. To identify proteins whose expression is regulated by injury in an mTOR-dependent manner, we analyzed the protein composition of DRGs from mice in which we genetically activated mTOR and from mice with or without a prior nerve injury. Quantitati…

An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer

2008

Abstract Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy–based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor–positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor–positive cancers. Unlike AKT1 mutations that were absent …

Longitudinal CSF proteome profiling in mice to uncover the acute and sustained mechanisms of action of rapid acting antidepressant (2R,6R)-hydroxynor…

2021

Delayed onset of antidepressant action is a shortcoming in depression treatment. Ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapid-acting antidepressants. However, their mechanism of action remains unknown. In this study, we first described the anxious and depression-prone inbred mouse strain, DBA/2J, as an animal model to assess the antidepressant-like effects of ketamine and HNK in vivo. To decode the molecular mechanisms mediating HNK's rapid antidepressant effects, a longitudinal cerebrospinal fluid (CSF) proteome profiling of its acute and sustained effects was conducted using an unbiased, hypothesis-free mass spectrometry-based proteomics app…

ErbB-3 activation by NRG-1β sustains growth and promotes vemurafenib resistance in BRAF-V600E colon cancer stem cells (CSCs)

2015

Approximately 5-10% of metastatic colorectal cancers harbor a BRAF-V600E mutation, which is correlated with resistance to EGFR-targeted therapies and worse clinical outcome. Vice versa, targeted inhibition of BRAF-V600E with the selective inhibitor PLX 4032 (Vemurafenib) is severely limited due to feedback re-activation of EGFR in these tumors. Mounting evidence indicates that upregulation of the ErbB-3 signaling axis may occur in response to several targeted therapeutics, including Vemurafenib, and NRG-1β-dependent re-activation of the PI3K/AKT survival pathway has been associated with therapy resistance. Here we show that colon CSCs express, next to EGFR and ErbB-2, also significant amoun…

2015

AbstractLight absorption can trigger biologically relevant protein conformational changes. The light-induced structural rearrangement at the level of a photoexcited chromophore is known to occur in the femtosecond timescale and is expected to propagate through the protein as a quake-like intramolecular motion. Here we report direct experimental evidence of such ‘proteinquake’ observed in myoglobin through femtosecond X-ray solution scattering measurements performed at the Linac Coherent Light Source X-ray free-electron laser. An ultrafast increase of myoglobin radius of gyration occurs within 1 picosecond and is followed by a delayed protein expansion. As the system approaches equilibrium i…

Novel Cancer Chemotherapy Hits by Molecular Topology: Dual Akt and Beta-Catenin Inhibitors

2015

Background and purposeColorectal and prostate cancers are two of the most common types and cause of a high rate of deaths worldwide. Therefore, any strategy to stop or at least slacken the development and progression of malignant cells is an important therapeutic choice. The aim of the present work is the identification of novel cancer chemotherapy agents. Nowadays, many different drug discovery approaches are available, but this paper focuses on Molecular Topology, which has already demonstrated its extraordinary efficacy in this field, particularly in the identification of new hit and lead compounds against cancer. This methodology uses the graph theoretical formalism to numerically chara…

Photoemission time-of-flight spectromicroscopy of Ag nanoparticle films on Si(111)

2004

Abstract Time-of-flight photoemission electron microscopy was used to measure spatially resolved energy distribution curves of electrons emitted from Ag nanoparticle films with different mass thicknesses. Two-photon photoemission (2PPE) was induced by femtosecond laser pulse excitation with 3.1 eV photon energy and 200 fs pulse width. Regions of Ag nanoparticles with different average sizes and one region with a continuous 100 nm thick Ag film were deposited as a stepped wedge on a Si(1 1 1) substrate. Upon laser excitation the nanoparticle films exhibit a very high electron emission yield in the images, whereas the uncovered Si surface and the continuous Ag film are dark. The time-of-fligh…

Multiphoton photoemission electron microscopy using femtosecond laser radiation

2002

Abstract The interaction of intense, pulsed laser radiation with surfaces results in non-linear optical effects that are responsible for emission of electrons even if the photon energies are below the work function. In the present study, photoelectrons have been excited by means of femtosecond laser pulses from a frequency doubled Ti:sapphire laser with a photon energy of 3.1 eV. The spatial distribution of the photo emitted electrons was imaged using a photoemission electron microscope. All samples exhibit centres of enhanced second or higher order photoemission yield, so called ‘hot spots’. These ‘hot spots’ were preferentially excited with s-polarised light. This behaviour may be explain…