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The nuclear membrane organization of leukotriene synthesis.

ABSTRACT: Leukotrienes (LTs) are signaling molecules derived from arachidonic acid that initiate and amplify innate and adaptive immunity. In turn, how their synthesis is organized on the nuclear envelope of myeloid cells in response to extracellular signals is not understood. We define the supramolecular architecture of LT synthesis by identifying the activation-dependent assembly of novel multiprotein complexes on the outer and inner nuclear membranes of mast cells. These complexes are centered on the integral membrane protein 5-Lipoxygenase-Activating Protein, which we identify as a scaffold protein for 5-Lipoxygenase, the initial enzyme of LT synthesis. We also identify these complexes in mouse neutrophils isolated from inflamed joints. Our studies reveal the macromolecular organization of LT synthesis.

SUBMITTER: Mandal AK

PROVIDER: S-EPMC2629249 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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The nuclear membrane organization of leukotriene synthesis.

Mandal Asim K AK Jones Phillip B PB Bair Angela M AM Christmas Peter P Miller Douglas D Yamin Ting-ting D TT Wisniewski Douglas D Menke John J Evans Jilly F JF Hyman Bradley T BT Bacskai Brian B Chen Mei M Lee David M DM Nikolic Boris B Soberman Roy J RJ

Proceedings of the National Academy of Sciences of the United States of America 20081215 51

Leukotrienes (LTs) are signaling molecules derived from arachidonic acid that initiate and amplify innate and adaptive immunity. In turn, how their synthesis is organized on the nuclear envelope of myeloid cells in response to extracellular signals is not understood. We define the supramolecular architecture of LT synthesis by identifying the activation-dependent assembly of novel multiprotein complexes on the outer and inner nuclear membranes of mast cells. These complexes are centered on the i ...[more]

PMID: 19075240

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Project description:PurposeHere, we examined the role of leukotrienes, well-known inflammatory mediators, in the tumorigenesis of hedgehog pathway-associated medulloblastoma, and tested the efficacies of antagonists of leukotriene biosynthesis in medulloblastoma treatment.Experimental Design: We examined the leukotriene levels in medulloblastoma cells by ELISA. We next tested whether leukotriene synthesis in medulloblastoma cells relied on activation of hedgehog pathway, or the presence of hedgehog ligand secreted by astrocytes. We then investigated whether leukotriene mediated hedgehog-induced Nestin expression in tumor cells. The functions of leukotriene in tumor cell proliferation and tumor growth in medulloblastoma were determined through knocking down 5-lipoxygenase (a critical enzyme for leukotriene synthesis) by shRNAs, or using 5-lipoxygenase-deficient mice. Finally, the efficacies of antagonists of leukotriene synthesis in medulloblastoma treatment were tested in vivo and in vitro.ResultsLeukotriene was significantly upregulated in medulloblastoma cells. Increased leukotriene synthesis relied on hedgehog ligand secreted by astrocytes, a major component of medulloblastoma microenvironment. Leukotriene stimulated tumor cells to express Nestin, a cytoskeletal protein essential for medulloblastoma growth. Genetic blockage of leukotriene synthesis dramatically suppressed medulloblastoma cell proliferation and tumor growth in vivo. Pharmaceutical inhibition of leukotriene synthesis markedly repressed medulloblastoma cell proliferation, but had no effect on proliferation of normal neuronal progenitors. Moreover, antagonists of leukotriene synthesis exhibited promising tumor inhibitory efficacies on drug-resistant medulloblastoma.ConclusionsOur findings reveal a novel signaling pathway that is critical for medulloblastoma cell proliferation and tumor progression, and that leukotriene biosynthesis represents a promising therapeutic target for medulloblastoma treatment.

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The nuclear membrane organization of leukotriene synthesis.

Publications

The nuclear membrane organization of leukotriene synthesis.

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