From bench to bedside: a diagnostics framework for pharmacogenetics research.

David A Katz

doi:10.1016/s1096-7192(02)00143-9

Home/Archive/PubMed

PubMed · 12359130

From bench to bedside: a diagnostics framework for pharmacogenetics research.

David A Katz

View original source ↗Export metadata ↓

Abstract

Although many genetic variants have been associated with differential drug responses, a very limited number of pharmacogenetic tests have entered common clinical practice. Pharmacogenetic tests that are successful address unmet medical needs, are clinically relevant, and have sufficient sensitivity, and specificity. In this respect, pharmacogenetics is no different from other diagnostics fields. Unmet medical need, clinical relevance, sensitivity, and specificity are discussed in the context of specific pharmacogenetic associations. These parameters are useful guides for researchers interested in translating pharmacogenetic findings from the bench to the bedside.

Explore related subjects

Arachidonate 5-Lipoxygenase Gene Amplification Genes, erbB-2 Humans Pharmacogenetics Polymorphism, Genetic Promoter Regions, Genetic Research Design Journal Article Review

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

David A Katz. From bench to bedside: a diagnostics framework for pharmacogenetics research.. https://doi.org/10.1016/s1096-7192(02)00143-9

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2007

ERK1/2 regulates two sequential steps promoting monocyte survival to peroxynitrite.

Previous studies from our laboratory indicate that cytosolic phospholipase A(2) (cPLA(2))-released arachidonic acid promotes monocyte/macrophage survival in the presence of peroxynitrite. In particular, the lipid messenger is metabolised by 5-lipoxygenase (5-LO) to 5-hydroxyeicosatetraenoic acid and causes the mitochondrial translocation of protein kinase Calpha (PKCalpha), an event associated with the cytosolic accumulation of Bad and Bax. Here we show that phosphorylation reactions driven by extracellular regulated kinase 1/2 (ERK1/2) critically regulate the activation/nuclear translocation of 5-LO. Inhibition of ERK1/2 was invariably associated with the cytosolic localisation of PKCalpha, the mitochondrial accumulation of Bad and Bax and with a rapid mitochondrial permeability transition-dependent necrosis. All these events were prevented by nanomolar concentrations of 5-hydroxyeicosatetraenoic acid. Hence, in addition to the previously characterised effects on cPLA(2), ERK1/2 critically regulates 5-LO activity in the absence of additional downstream targets in the survival signalling preventing peroxynitrite toxicity.

Arachidonate 5-Lipoxygenase↗

PubMed2006

Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A4 production.

Regulation of 5-lipoxygenase (5LO) activity is a key determinant for the biosynthesis of proinflammatory leukotrienes. Coactosin-like protein (CLP) is an F-actin-binding protein that can also bind 5LO. Here, we report that CLP can up-regulate and modulate 5LO activity [formation of 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HPETE)], 5(S)-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HETE), and 5(S)-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid (LTA(4)) in vitro. Three findings are presented. First, CLP up-regulates Ca(2+)-induced 5LO activity, in the absence of phosphatidylcholine (membrane). Apparently, CLP can function as a scaffold for 5LO, similar to membranes. Second, CLP gives a considerable (3-fold) increase in the amount of LTA(4) formed by 5LO, when present together with phosphatidylcholine. Third, CLP increases the ratio of 5-HETE/5-HPETE. These effects require protein interaction by Trp residues in ligand-binding loops of the 5LO beta-sandwich; both binding and stimulatory effects of CLP were abolished for the mutant 5LO-W13/75/102A. In polymorphonuclear leukocytes stimulated with Ca(2+) ionophore, both CLP and 5LO associated with the nucleus, whereas in resting cells, CLP and 5LO were cytosolic. These findings establish CLP as a factor relevant for 5LO product formation. Functioning as a 5LO scaffold, CLP may provide a basis for the formation of 5-HETE in the cytosol of different cell types. Furthermore, in stimulated cells, CLP appears to function in a complex together with 5LO and membranes, increasing the capacity of 5LO for leukotriene biosynthesis.

Arachidonate 5-Lipoxygenase↗

PubMed2006

The coding sequence mediates induction of 5-lipoxygenase expression by Smads3/4.

5-Lipoxygenase (5-LO) expression is strongly induced by transforming growth factor-beta (TGFbeta) and 1alpha,25-dihydroxyvitamin D(3) in Mono Mac 6 cells. Since Smads have been described as downstream effectors of TGFbeta, we have investigated the role of the TGFbeta/Smad signalling system in the regulation of 5-LO gene expression. The rapid induction of 5-LO mRNA, determined with real-time quantitative RT-PCR, suggests that 5-LO is a primary TGFbeta target gene. In reporter gene assays with plasmids containing the 5-LO promoter plus different parts of the gene, Smads3/4 mediate a prominent upregulation of reporter activity that strongly depends on the coding sequence and to a lesser extent on the 3'-UTR and introns J-M. Deletion studies revealed the most profound decrease of inducibility by Smads3/4 when exons 10-14 are deleted. Sequence analysis and deletion studies indicate the existence of up to four Smad binding elements and at least one TGFbeta responsive element far downstream of the transcriptional start site.

Arachidonate 5-Lipoxygenase↗