Push-pull forces of innovative drug discovery.

Pushing the pharmaceutical industry to improve its performance, are years of poor returns on investment in research and development as well as the patients' advocacy for their unmet medical needs. Pulling on our industry, we find an exploding scientific knowledge of disease mechanisms and the translation of this information into treatments by innovative biotechnology companies. Those companies that manage best these push-pull forces - in particular, the therapies provided by biotechnology - will succeed in creating the innovative medicines of tomorrow.

Distamycin prolongs E-selectin expression by interacting with a specific NF-kappaB-HMG-I(Y) binding site in the promoter.

The E-selectin cell adhesion protein plays a critical role in mediating adherence of leukocytes to endothelium at sites of inflammation. Cytokine-induced E-selectin expression on the surface of endothelial cells is transient; mRNA expression peaks at 3-4 h after induction and returns to basal levels within 24 h. The mechanism for this transcriptional down-modulation is not known.

Commonly used cat reporter vectors contain a cAMP-inducible, cryptic enhancer that co-operates with NF-kappa B-sites.

Commercially available and widely used cat expression vectors were found to contain a forskolin (Fs)-inducible element capable of co-operation with NF-kappa B-sites in test promoters. An alternative NF-kappa B-dependent reporter system is presented that allows investigation of the effects of Fs and other agents that augment intracellular cyclic AMP.

Transcription factor-induced, phased bending of the E-selectin promoter.

E-selectin is an endothelial adhesion molecule that is critically involved in neutrophil adhesion and recruitment. All DNA elements required for interleukin-1 inducibility have been located in the proximal promoter: an NF-ELAM1/ATF site, two NF-kappa B sites (I and II), the NF-ELAM2 element and a TATA box. We show here that interleukin-1 induced promoter activity is exquisitely sensitive to the spatial arrangements of these elements.