Biomedical subjects

Doriane Trompier

Publications and source records attributed to Doriane Trompier.

6 recordsLinked to original sources

PubMed2006

Cooperation between engulfment receptors: the case of ABCA1 and MEGF10.

The engulfment of dying cells is a specialized form of phagocytosis that is extremely conserved across evolution. In the worm, it is genetically controlled by two parallel pathways, which are only partially reconstituted in mammals. We focused on the recapitulation of the CED-1 defined pathway in mammalian systems. We first explored and validated MEGF10, a novel receptor bearing striking structural similarities to CED-1, as a bona fide functional ortholog in mammals and hence progressed toward the analysis of molecular interactions along the corresponding pathway. We ascertained that, in a system of forced expression by transfection, MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. Indeed, the coexpression of either a functional or a mutant ABCA1 exerted a transdominant positive or negative modulation on the MEGF10-dependent engulfment. The combined use of biochemical and biophysical approaches indicated that this functional cooperation relies on the alternate association of these receptors with a common partner, endogenously expressed in our cell system. We provide the first working model structuring in mammals the CED-1 dependent pathway.

ATP Binding Cassette Transporter 1↗

PubMed2006

ABCA1, from pathology to membrane function.

The ABCA1 transporter is the prototype of the A class of mammalian adenosine triphosphate binding cassette transporters and one of the largest members of this family. ABCA1 has been originally identified as an engulfment receptor on macrophages and, more recently, it has been shown to play an essential role in the handling of cellular lipids. Indeed by promoting the effluxes of membrane phospholipids and cholesterol to lipid-poor apoprotein acceptors, ABCA1 controls the formation of high-density lipoproteins and thus the whole process of reverse cholesterol transport. A number of additional phenotypes have been found in the mouse model of invalidation of the ABCA1 gene. In spite of their clinical diversity, they all are extremely sensitive to variations in the physicochemical properties of the cell membrane, which ABCA1 controls as a lipid translocator.

ATP Binding Cassette Transporter 1↗

PubMed2006

Transition from dimers to higher oligomeric forms occurs during the ATPase cycle of the ABCA1 transporter.

Fluorescence resonance energy transfer and native PAGE analytical techniques were employed to assess the quaternary structure of ABCA1, an ATP binding cassette transporter playing a crucial role in cellular lipid handling. These experimental approaches support the conclusion that ABCA1 is associated in dimeric structures that undergo transition into higher order structures, i.e. tetramers, during the ATP catalytic cycle. Our data hence underline molecular assembly as a crucial parameter in ABCA1 function and the advantage of native PAGE as analytical tool for intractable membrane proteins.

ATP Binding Cassette Transporter 1↗

PubMed2005

Anticancer multidrug resistance mediated by MRP1: recent advances in the discovery of reversal agents.

Multidrug resistance protein 1 (MRP1) belongs to the ATP-binding cassette (ABC) transporter family. It is able to transport a broad range of anticancer drugs through cellular membranes, thus limiting their antiproliferative action. Since its discovery in 1992, MRP1 has been the most studied among MRP proteins, which now count nine members. Besides the biological work, which targets structure elucidation, binding sites location, and mode of action, most efforts have been focused on finding molecules which act as MRP1 inhibitors. In this review, we attempt to summarize and highlight studies dealing with modulators of MRP1-mediated multidrug resistance (MDR), which have been accomplished in the last 5 years. The reported MRP1 inhibitors are discussed according to their chemical class. Finally, we try to bring information on structure-activity relationship (SAR) aspects and how modulators might interact with MRP1. This study may facilitate the rational design of future modulators of MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Verapamil and its derivative trigger apoptosis through glutathione extrusion by multidrug resistance protein MRP1.

This study demonstrates that verapamil and a newly synthesized verapamil derivative, NMeOHI(2), behave as apoptogens in multidrug resistance protein 1 (MRP1)-expressing cells. When treated with either verapamil or NMeOHI(2), surprisingly, baby hamster kidney-21 (BHK) cells transfected with human MRP1 were killed. Because parental BHK cells were not, as well as cells expressing an inactive (K1333L) MRP1 mutant, this indicated that cell death involved functional MRP1 transporter. Cell death was identified as apoptosis by using annexin V-fluorescein labeling and was no longer observed in the presence of the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH(2)F (Z-VAD-FMK). In vitro, both verapamil and its derivative inhibited leukotriene C4 transport by MRP1-enriched membrane vesicles in a competitive manner, with a K(i) of 48.6 microm for verapamil and 5.5 microm for NMeOHI(2,) and stimulated reduced glutathione (GSH) transport 3-fold and 9-fold, respectively. Treatment of MRP1-expressing cells with either verapamil or the derivative quickly depleted intracellular GSH content with a strong decrease occurring in the first hour of treatment, which preceded cell death beginning at 8-16 h. Furthermore, addition of GSH to the media efficiently prevented cell death. Therefore, verapamil and its derivative trigger apoptosis through stimulation of GSH extrusion mediated by MRP1. This new information on the mechanism of induced apoptosis of MDR cells may represent a novel approach in the selective treatment of MRP1-positive tumors.

Animals↗

PubMed2002

4-Hydroxy-6-methoxyaurones with high-affinity binding to cytosolic domain of P-glycoprotein.

A series of 4-hydroxy-6-methoxyaurones and 4,6-dimethoxyaurones has been synthesised and tested for their binding affinity toward the nucleotide-binding domain of P-glycoprotein, an ABC (ATP-Binding Cassette) transporter which mediates the resistance of cancer cells to chemotherapy. These compounds differ from each other by the nature of the substituent on the aurone B-ring. The binding affinity seems to be linked to the nature of the substituent, as well as to the presence or the absence of a hydroxy group at position 4. The most active compounds were 4'-bromo-4-hydroxy-6-methoxyaurone and 4-hydroxy-4'-iodo-6-methoxyaurone.

ATP Binding Cassette Transporter, Subfamily B, Mem↗