DNA microarray technology and antimicrobial drug discovery.

The genomics era is providing us with vast amounts of information derived from whole-genome sequencing. This will doubtlessly revolutionise biology and the way novel medicines will be discovered. To leverage this information efficiently, however, technologies in addition to high-throughput sequencing are required.

Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity.

The VHL tumor suppressor gene has previously been reported to encode a protein of 213 amino acid residues. Here we report the identification of a second major VHL gene product with an apparent molecular weight of 18 kD, pVHL18, which appears to arise from alternate translation initiation at a second AUG codon (codon 54) within the VHL open reading frame. In vitro and in vivo studies indicate that the internal codon in the VHL mRNA is necessary and sufficient for production of pVHL18.

PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes.

Exposure of mammalian cells to hypoxia, radiation and certain chemotherapeutic agents promotes cell cycle arrest and/or apoptosis. Activation of p53 responsive genes is believed to play an important role in mediating such responses. In this study we identified a novel gene, PA26, which maps to chromosome 6q21 and encodes at least three transcript isoforms, of which two are differentially induced by genotoxic stress (UV, gamma-irradiation and cytotoxic drugs) in a p53-dependent manner.

The p53/IGF-1 receptor axis in the regulation of programmed cell death.

The loss or functional inactivation of tumor suppressor genes appears to be one of the most fundamental genetic mechanisms of tumorigenesis, and rational insights into the signaling pathways of tumor suppressor genes have emerged as a successful strategy of identifying novel drug discovery targets downstream of the tumor suppressor protein itself. Elucidation of novel pathways downstream of p53 have established a link between this important tumor suppressor gene and the insulin-like growth factor-1 receptor (IGF-1r), either via direct regulation of IGF-1 receptor levels, or modulation of IGFs via transactivation of the insulin-like growth factor-binding protein 3 (IGF-BP3) gene. Binding of IGF-BP3 to IGFs inhibits both their mitogenic and cell survival functions, highlighting a novel pathway whereby p53 may regulate apoptosis in tumor cells.