George S. Johnson

Since 1990, the National Cancer Institute (NCI) has screened more than 60,000 compounds against a panel of 60 human cancer cell lines. The 50-percent growth-inhibitory concentration (GI50) for any single cell line is simply an index of cytotoxicity or cytostasis, but the patterns of 60 such GI50 values encode unexpectedly rich, detailed information on mechanisms of drug action and drug resistance. Each compound's pattern is like a fingerprint, essentially unique among the many billions of distinguishable possibilities. These activity patterns are being used in conjunction with molecular structural features of the tested agents to explore the NCI's database of more than 460,000 compounds, and they are providing insight into potential target molecules and modulators of activity in the 60 cell lines. For example, the information is being used to search for candidate anticancer drugs that are not dependent on intact p53 suppressor gene function for their activity. It remains to be seen how effective this information-intensive strategy will be at generating new clinically active agents.

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size ...Read More

Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance the survival potential of latently infected B cells in vitro through up-regulation of the cellular survival protein Bcl-2. The possibility that an analogous effect is operative in lytically infected cells was suggested by the observation of distant sequence homology between an Epstein-Barr virus-coded early lytic cycle protein, BHRF1, and Bcl-2. Here we show by gene transfer that BHRF1 resembles Bcl-2 both in its subcellular localization and in its capacity to enhance B-cell survival. Thus confocal microscopic analysis of cells acutely cotransfected with BHRF1 and Bcl-2 expression vectors revealed substantial colocalization of the two proteins in the cytoplasm. In subsequent experiments, stable BHRF1 gene transfectants of Burkitt lymphoma cells paralleled Bcl-2 transfectants in their enhanced survival under conditions that induce cell death by apoptosis. Despite their limited sequence conservation, therefore, the two proteins appear to be functionally homologous. We suggest that BHRF1 provides an alternative, Bcl-2-independent, means of enhancing B-cell survival that may operate during the virus lytic cycle.

Sarcoma cells growing in tissue culture have morphological and growth characteristics different than normal fibroblasts. Several of the morphological characteristics of normal fibroblasts are regained when the cells are incubated with dibutyryl-cyclic AMP or butyryl-cyclic AMP (0.1-1 mM), or cyclic AMP (3 mM) plus theophylline (1 mM), but not with ATP, ADP, AMP, adenine, or adenosine (1-7 mM). The cell bodies become elongated; distinct narrow processes are formed. With prolonged incubation, the cells show less tendency to pile up or become polygonal. Further, L-929 and Rous sarcomatransformed hamster cells orient in parallel arrays characteristic of contact inhibition. The cells retain their altered morphology as long as the butyryl-cyclic AMP is present, but revert after its removal. Experiments with cycloheximide, puromycin, and actinomycin D indicate that protein Synthesis, but not RNA synthesis, is required for the response. Microtubular proteins may be involved. No response is observed with normal fibroblasts or with various epithelial cells. The data suggest that cyclic AMP may be an important factor in the determination of morphology of normal fibroblasts and this function may be lost or altered during transformation.