PubMed · 12563039
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Laurence A Boxer. 2003. Neutrophil abnormalities.. https://doi.org/10.1542/pir.24-2-52
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Cancer is viewed as a multistep process whereby a normal cell is transformed into a cancer cell through the acquisition of mutations. We reduce the complexities of cancer progression to a simple set of underlying rules that govern the transformation of normal cells to malignant cells. In doing so, we derive an ordinary differential equation model that explores how the balance of angiogenesis, cell death rates, genetic instability, and replication rates give rise to different kinetics in the development of cancer. The key predictions of the model are that cancer develops fastest through a particular ordering of mutations and that mutations in genes that maintain genomic integrity would be the most deleterious type of mutations to inherit. In addition, we perform a sensitivity analysis on the parameters included in the model to determine the probable contribution of each. This paper presents a novel approach to viewing the genetic basis of cancer from a systems biology perspective and provides the groundwork for other models that can be directly tied to clinical and molecular data.
Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been proposed as a novel therapy to treat type 2 diabetes and obesity. In order to identify novel PTP1B inhibitors, we have developed a robust screen in Saccharomyces cerevisiae where growth is dependent on PTP1B catalytic activity. This was based on the observation that overexpression of v-Src, a tyrosine kinase, in yeast leads to lethality through mitotic dysfunction and this lethality can be reversed by co-expression of PTP1B. The expression levels of v-Src and PTP1B were optimized to obtain a balance between robust growth and sensitivity to inhibitors. Screening was carried out in 96-well plates and growth of the liquid culture measured by absorbance at 600 nm. Initial characterization was performed using vanadate as well as some novel PTP1B inhibitors. Vanadate specifically inhibited PTP1B-dependent growth in a dose dependent manner with an EC50 of 0.92 +/- 0.07 mM. This simple yeast growth interference assay has the potential for use as a high throughput screen for PTP1B inhibitors in sample collections or crude mixtures.