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James Leonard

Publications and source records attributed to James Leonard.

5 recordsLinked to original sources
PubMed2004

Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein.

Ethylmalonic encephalopathy (EE) is a devastating infantile metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels. High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle. By use of a combination of homozygosity mapping, integration of physical and functional genomic data sets, and mutational screening, we identified GenBank D83198 as the gene responsible for EE. We also demonstrated that the D83198 protein product is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The gene had previously been known as "HSCO" (for hepatoma subtracted clone one). However, given its role in EE, the name of the gene has been changed to "ETHE1." The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism.

Amino Acid Sequence↗
PubMed2004

Orphan GPCR target validation.

Nearly half of the identified non-olfactory G protein-coupled receptors (GPCRs) have no identified cognate ligand. These 'orphan' receptors are likely to have important physiological roles that could potentially be exploited therapeutically. However, by definition, such receptors are not immediately open for pharmacological investigation of their function. Here we summarize several strategic approaches to facilitate the discovery of orphan GPCR biology.

Animals↗
PubMed2003

Twist is up-regulated in response to Wnt1 and inhibits mouse mammary cell differentiation.

Wnt1, initially identified as a mammary oncogene, can activate transcription via beta-catenin/TCF complexes. Twist, a transcription factor of the basic helix-loop-helix class, has also been suggested to have oncogenic properties. The aim of this study was to determine whether Twist is regulated by Wnt1 and might thus be a novel mediator of Wnt signaling. We found that Twist was up-regulated in C57MG and HC11 murine mammary epithelial cells in response to Wnt1 expression. Additionally, we detected Twist expression in normal mammary gland and found elevated Twist expression in approximately 70% of mammary tumors from Wnt1 transgenic mice. A murine Twist promoter fragment was shown to be responsive to beta-catenin, and its activity was enhanced by coexpression of c-jun and Ets factors of the PEA3 family. Both PEA3 factors and c-jun were highly expressed in tumors from Wnt1 transgenic mice and may therefore contribute to the increased Twist expression observed in these tumors. To evaluate functional consequences of Twist induction, we examined the effect of Twist on mammary cell differentiation. Strikingly, overexpression of either Wnt1 or Twist in HC11 mammary epithelial cells completely suppressed induction of the milk protein beta-casein in response to lactogenic hormones. Additionally, Wnt1, but not Twist, partially abrogated induction of WDNM1, another marker of lactogenic differentiation. Taken together, our data indicate that Twist expression is regulated by Wnt/beta-catenin signaling and that both Wnt1 and Twist can function as inhibitors of lactogenic differentiation, an effect that could contribute to mammary tumorigenesis.

Animals↗