KATs in cancer: functions and therapies.

Post-translational acetylation of lysines is most extensively studied in histones, but this modification is also found in many other proteins and is implicated in a wide range of biological processes in both the cell nucleus and the cytoplasm. Like phosphorylation, acetylation patterns and levels are often altered in cancer, therefore small molecule inhibition of enzymes that regulate acetylation and deacetylation offers much potential for inhibiting cancer cell growth, as does disruption of interactions between acetylated residues and 'reader' proteins. For more than a decade now, histone deacetylase inhibitors have been investigated for their ability to increase acetylation and promote expression of tumor suppressor genes.

Protein-arginine methyltransferase 1 (PRMT1) methylates Ash2L, a shared component of mammalian histone H3K4 methyltransferase complexes.

Multiple enzymes and enzymatic complexes coordinately regulate the addition and removal of post-translational modifications on histone proteins. The oncoprotein Ash2L is a component of the mixed lineage leukemia (MLL) family members 1-4, Setd1A, and Setd1B mammalian histone H3K4 methyltransferase complexes and is essential to maintain global trimethylation of histone H3K4. However, regulation of these complexes at the level of expression and activity remains poorly understood.

2 The family of protein arginine metkyltransferases.

Arginine methylation is a widespread posttranslational modification found on both nuclear and cytoplasmic proteins. The methylation of arginine residues is catalyzed by the protein arginine N-methyltransferase (PRMT) family of enzymes, of which there are at least nine members in mammals. PRMTs are evolutionarily conserved and are foundin organisms from yeast to man, but not in bacteria.

Molecular characterization of glycogen storage disease type III.

Deficiency of the glycogen debranching enzyme (gene, AGL) causes glycogen storage disease type III (GSD-III), an autosomal recessive disease affecting glycogen metabolism. Most GSD-III patients have AGL deficiency in both the liver and muscle (type IIIa), but some have it in the liver but not muscle (type IIIb). Cloning of human AGL cDNAs and determination of the genomic structure and mRNA isoforms of AGL have allowed for the study of GSD-III at the molecular level.

Role of intracellular interleukin-1 receptor antagonist in skin carcinogenesis.

Interleukin 1 (IL-1) is a major mediator of inflammation and exerts pleiotropic effects on many systems. To elucidate the role of its endogenous inhibitor, intracellular IL-1 receptor antagonist (icIL-1Ra), in mouse skin, we produced an icIL-1Ra-overexpressing skin carcinoma cell line (icIL-1Ra-JWF2). Altered expression of icIL-1Ra did not change IL-1alpha mRNA levels in these transfected cells.

Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma.

Objective: Uterine leiomyoma are the most common gynecologic neoplasm and a primary cause of hysterectomy in premenopausal women. Preclinical studies were conducted in the Eker rat model to investigate the potential efficacy of selective estrogen receptor modulators (SERMs) as therapeutic agents for this tumor.

Methods: Twelve-month-old Eker rats were randomized into five treatment arms including tamoxifen, placebo, LY 326315, vehicle, and no treatment.

Preclinical toxicity study of intrathecal administration of the pain relievers dextrorphan, dextromethorphan, and memantine in the sheep model.

Objectives To determine the toxicity window for the continuous intrathecal administration of dextrorphan, dextromethorphan, and memantine via an implanted delivery pump. Materials and Methods Using 48 sheep with programmable continuous intrathecal infusion systems we determined the behavioral, motor, neurological, and histopathological changes produced by a 43-day continuous infusion study of dextrorphan, dextromethorphan, and memantine dissolved in 0.9% NaCl.

Involvement of a pertussis-toxin sensitive G protein in the induction of gene expression by insulin.

Binding of insulin to its receptor triggers multiple cellular responses, including changes in metabolism and in gene expression, resulting from the activation of multiple signalling pathways. Pertussis toxin has been shown to block an insulin-stimulated phospholipase C, resulting in an inhibition of the synthesis of phospholipid second messengers by insulin. In the present study, we investigated the significance of this pathway for the induction of growth-related genes by insulin treatment of H35 hepatoma cells.

Model life table for captive chimpanzees.

Mortality statistics from three captive populations of chimpanzees (Pan troglodytes) were combined to generate standard model life tables for each sex in this species. The model is compared to an estimate of survivorship of a group of wild animals, and is applied to an incomplete data set to illustrate how the model may be used to extend estimates of mortality statistics to missing older ages. © 1995 Wiley-Liss, Inc.

(C-A)n microsatellite repeat D7S522 is the most commonly deleted region in human primary breast cancer.

Loss of heterozygosity in human chromosome 7q was studied to determine the location of a putative tumor suppressor gene. Twenty-six of 31 cases studied presented loss of heterozygosity at one or more loci on chromosome 7q. Eighty-three percent loss of heterozygosity (in 11 informative cases) was detected by using the (C-A)n microsatellite repeat marker D7S522 at 7q31.

Inhibition of tumorigenicity of a murine squamous cell carcinoma (SCC) cell line by a putative tumor suppressor gene on human chromosome 7.

Alterations in oncogenes and tumor suppressor genes (TSG) are considered to be critical steps in oncogenesis. However information on putative TSG involved in the development of squamous cell carcinomas (SCC) is very limited. In this study we confirmed the existence of a tumor suppressor gene (TSG) on human chromosome 7 (hchr 7) that suppresses the tumorigenicity of squamous cell carcinomas (SCCs).

Abnormal behaviors, with a special focus on rocking, and reproductive competence in a large sample of captive chimpanzees (Pan troglodytes).

Chimpanzees (Pan troglodytes) are endangered in the wild and may no longer be imported into the United States. Of those animals presently in captivity, candidates for breeding programs must be identified to insure a self-sustaining captive population. Some have suggested that poor reproductive performance might be linked to the performance of abnormal behaviors.