Autocrine regulation of human urothelial cell proliferation and migration during regenerative responses in vitro.

Regeneration of the urothelium is rapid and effective in order to maintain a barrier to urine following tissue injury. Whereas normal human urothelial (NHU) cells are mitotically quiescent and G0 arrested in situ, they rapidly enter the cell cycle upon seeding in primary culture and show reversible growth arrest at confluency. We have used this as a model to investigate the role of EGF receptor signaling in urothelial regeneration and wound-healing.

Effects of loss of p53 and p16 function on life span and survival of human urothelial cells.

Human urothelial cell carcinoma evolves via the accumulation of numerous genetic alterations, with loss of p53 and p16 function representing important stages in the development of superficial lesions and their progression to malignant disease. To investigate the effects of disabling either or both proteins in otherwise normal human urothelial cells, we performed retroviral transductions with a dominant negative p53 miniprotein and/or mutant cyclin-dependent kinase 4 (CDK4R24C) in 3 independent cell lines. Although cells with disabled p53 function showed a higher proliferation rate, inactivation of neither p53 nor p16 function resulted in any extension of life span and the double-transductants failed to flourish, demonstrating that further genetic alterations are required to attain an immortalised phenotype.

Synthesis of jaspaquinol and effect on viability of normal and malignant bladder epithelial cell lines.

The synthesis of jaspaquinol 1, a monocyclic diterpene-benzenoid, is reported. Two synthetic routes to this natural product have been developed. The first, utilises a difunctional terpene derivative containing different leaving groups, facilitating the selective introduction of the cyclohexenyl and benzenoid fragments.