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AAMP and MTSS1 are novel negative regulators of endothelial barrier function identified in a proteomics screen

ABSTRACT: Primary HUVEC were treated with 500 nM MLN7243, 500 nM MLN4924 or DMSO (control) for 6 h. The experiment aims to identify up- or downregulated proteins after treatment with the E1 ligase inhibitor MLN7243 and the cullin inhibitor MLN4924 in HUVEC. Proteins that are regulated by ubiquitination or more specifically by cullin-based E3 ligases in the quiescent endothelium, will be identified.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Thang Pham

LAB HEAD: Connie Jimenez

PROVIDER: PXD053910 | Pride | 2025-05-07

REPOSITORIES: Pride

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			Action	DRS
	QE1_220422_OPL3024_FP_HUVEC_Tx_A.raw	Raw
	QE1_220422_OPL3024_FP_HUVEC_Tx_B.raw	Raw
	QE1_220422_OPL3024_FP_HUVEC_Tx_C.raw	Raw
	QE1_220422_OPL3024_FP_HUVEC_Tx_D.raw	Raw
	QE1_220422_OPL3024_FP_HUVEC_Tx_E.raw	Raw

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Publications

AAMP and MTSS1 Are Novel Negative Regulators of Endothelial Barrier Function Identified in a Proteomics Screen.

Podieh Fabienne F Overboom Max C MC Knol Jaco C JC Piersma Sander R SR Goeij-de Haas Richard R Pham Thang V TV Jimenez Connie R CR Hordijk Peter L PL

Cells 20240925 19

Cell-cell adhesion in endothelial monolayers is tightly controlled and crucial for vascular integrity. Recently, we reported on the importance of fast protein turnover for maintenance of endothelial barrier function. Specifically, continuous ubiquitination and degradation of the Rho GTPase RhoB is crucial to preserve quiescent endothelial integrity. Here, we sought to identify other barrier regulators, which are characterized by a short half-life, using a proteomics approach. Following short-ter ...[more]

PMID: 39404373

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Expression data from ependymal cell cultures treated with MLN4924.

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Gene expression profiles of myeloma cells treated with NAE inhibitor

Project description:The transcriptional profile of the human multiple myeloma (MM) cell line MM.1S treated with MLN4924 vs control MM.1S cells was characterized by oligonucleotide microarray analysis, using the human U133 plus 2.0 Affymetrix GeneChip, according to previously described protocols for total RNA extraction and purification; cDNA synthesis; in vitro transcription reaction for production of biotin-labeled cRNA; hybridization of cRNA with U133plus2.0 Affymetrix gene chips; and scanning of image output files. Scanned image output files were analyzed using DNA-Chip Analyzer (dChip) (www.dchip.org), including conversion to DCP files, normalization and modeling. The gene expression profile of MM.1S cells for each time point of MLN4924 treatment was compared to the profile of control MM.1S cells. The NEDD8 activating enzyme (NAE) is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases (CRLs), which regulate degradation of a distinct subset of proteins. The more targeted impact of NAE on protein degradation prompted us to study MLN4924, an investigational NAE inhibitor, in preclinical multiple myeloma (MM) models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability in a panel of human MM cell lines. In this analysis, we evaluated the molecular changes triggered in MM.1S myeloma cells by their in vitro treatment with MLN4924. The transcriptional profiles of each experimental condition were characterized by oligonucleotide microarray analysis, using the human U133 plus 2.0 Affymetrix GeneChip. The human multiple myeloma (MM) cells MM.1S were cultured in vitro in the presence or absence of the NEDD8 activating enzyme (NAE) inhibitor MLN4924 for 8, 16 or 24hrs. The gene expression profiles of drug treated cells were compared with the profiles of control MM.1S cells.

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2022-03-29 | PXD024426 | Pride

HiRIEF-LC-MS based proteomics on Small Intestinal Neuroendocrine Tumors (SI-NET) and SI-NET cell lines

Project description:Associated to PXD009877 which contains Part I and Part II. Part III – Pevonedistat/MLN4924 and Bortezomib treatment of the SI-NET (small intestinal – neuroendocrine tumor) cell line CNDT2. High Resolution Isoelectric Focusing (HiRIEF) LC-MS and relative quantification by TMT 10-plex was used to analyze cellular response to the proteasome inhibitor Bortezomib alone or in combination with the neddylation inhibitor pevonedistat (MLN4924) at 12h after treatment in the CNDT2 cell line. The data was obtained from one TMT 10-plex experiment which included 4 untreated controls (TMT channels 126, 127N, 127C and 128N), 3 samples treated with 500 nM Bortezomib for 12 hours (TMT channels 128C, 129N and 129C) as well as 3 samples treated with both Bortezomib and Pevonedistat at 500 nM respectively for 12 hours (TMT channels 130N, 130C and 131).

2021-06-10 | PXD013024 | Pride

The COP9 signalosome reduces neuroinflammation and attenuates ischemic neuronal stress in organotypic brain slice culture model

Project description:In the context of studying the role of the COP9 signalosome (CSN) in neuroinflammation and ischemic neuronal damage, we studied the effect of the cullin NEDDylation state-modifying drugs MLN4924 and CSN5i-3 in BV2 microglial cells, an immortalized murine cell line featuring many of the characteristics of primary microglia. Owing to its potent inhibitory effect on the NEDDylation cascade, MLN4924 exhibits a CSN5-like anti-inflammatory activity. Csn5i-3 is a small molecule inhibitor that specifically binds to CSN5, while it resides in the CSN holocomplex and blocks its deNEDDylase activity, thus leading to an accumulation of NEDDylated cullins. We performed untargeted mass spectrometry-based proteomics of the cell lysates after treating BV2 cells with these drugs under basal culture stress conditions. The proteomic analysis revealed that MLN4924 and CSN5i-3 substantially altered the microglial proteome.

2023-10-24 | PXD044650 | Pride

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