These results suggest that the clinical response to docetaxel can be predicted by gene expression patterns in biopsy samples. The results also suggest that one of the molecular mechanisms of the resistance is activation of a group of redox genes.

Microenvironment-based alterations in phenotypes of mast cells influence the susceptibility to anaphylaxis, yet the mechanisms underlying proper maturation of mast cells toward an anaphylaxis-sensitive phenotype are incompletely understood. Here we report that PLA2G3, a mammalian homolog of anaphylactic bee venom phospholipase A2, regulates this process. PLA2G3 secreted from mast cells is coupled with fibroblastic lipocalin-type PGD2 synthase (L-PGDS) to provide PGD2, which facilitates mast-cell maturation via PGD2 receptor DP1. Mice lacking PLA2G3, L-PGDS or DP1, mast cell–deficient mice reconstituted with PLA2G3-null or DP1-null mast cells, or mast cells cultured with L-PGDS–ablated fibroblasts exhibited impaired maturation and anaphylaxis of mast cells. Thus, we describe a lipid-driven PLA2G3–L-PGDS–DP1 loop that drives mast cell maturation.

We have recently shown that two distinct prostaglandin (PG) E 2 synthases show preferential functional coupling with upstream cyclooxygenase (COX)-1 and COX-2 in PGE 2 biosynthesis. To investigate whether other lineage-specific PG synthases also show preferential coupling with either COX isozyme, we introduced these enzymes alone or in combination into 293 cells to reconstitute their functional interrelationship. As did the membrane-bound PGE 2 synthase, the perinuclear enzymes thromboxane synthase and PGI 2 synthase generated their respective products via COX-2 in preference to COX-1 in both the A23187-induced immediate and interleukin-1-induced delayed responses. Hematopoietic PGD 2 synthase preferentially used COX-1 and COX-2 in the A23187-induced immediate and interleukin-1-induced delayed PGD 2 -biosynthetic responses, respectively. This enzyme underwent stimulus-dependent translocation from the cytosol to perinuclear compartments, where COX-1 or COX-2 exists. COX selectivity of these lineage-specific PG synthases was also significantly affected by the concentrations of arachidonate, which was added exogenously to the cells or supplied endogenously by the action of cytosolic or secretory phospholipase A 2 . Collectively, the efficiency of coupling between COXs and specific PG synthases may be crucially influenced by their spatial and temporal compartmentalization and by the amount of arachidonate supplied by PLA 2 s at a moment when PG production takes place.Biosynthesis of prostaglandins (PGs) 1 through the cyclooxygenase (COX) pathway involves oxidation and subsequent isomerization of membrane-derived arachidonic acid (AA) via three sequential enzymatic reactions. The initial step of this metabolic pathway is the stimulus-induced liberation of AA from membrane glycerophospholipids by the action of phospholipase A 2 (PLA 2 ) enzymes, including cytosolic PLA 2 ␣ (cPLA 2 ; group IVA) and several secretory PLA 2 (sPLA 2 ) isozymes (groups IIA, IID, V, and X) (1-10). The released AA is sequentially metabolized to PGG 2 and then to PGH 2 by either COX-1 or COX-2. PGH 2 is then converted to various bioactive PGs (thromboxane (TX) A 2 , PGD 2 , PGE 2 , PGF 2␣ , and PGI 2 ) by the respective terminal PG synthases, which have different structures and exhibit cell-and tissue-specific distributions.Segregated utilization of COX-1 and COX-2 in the PG biosynthetic events has been demonstrated by a number of cell biological, pharmacological, and genetic studies (3,(11)(12)(13)(14)(15)(16)(17). Generally, the constitutive COX-1 is mainly utilized in the immediate PG biosynthesis, which occurs within several minutes after stimulation with Ca 2ϩ mobilizers, whereas the inducible COX-2 is an absolute requirement for delayed PG biosynthesis, which lasts for several hours after proinflammatory stimuli. When cells are first treated with proinflammatory stimuli and subsequently exposed to Ca 2ϩ mobilizers, the induced COX-2 can also promote the immediate response (priming response) (3, 18 -22). However, the precise molecular me...

These findings indicate that the domain including the hydrophobic region of ATGL was essential for association with LDs.

No abstract