S. Sengupta et al., Tumour regression in a ligand inducible manner mediated by a chimeric tumour suppressor derived from p53, ONCOGENE, 19(3), 2000, pp. 337-350
The p53 tumour suppressor induces cell cycle arrest and apoptosis in respon
se to cellular stresses. p53 is inactivated by various cellular and viral f
actors. We set out to generate regulatable p53 derivatives that are highly
inducible by synthetic ligands, escape inactivation and efficiently induce
apoptosis. We have generated Ligand Inducible Chimeric Tumour Suppressors (
LICTS), that are inactive unless provided with artificial ligands. They are
resistant to inactivation, due to the replacement of domains that mediate
p53 inhibition by heterologous sequences. LICTS are activated by micromolar
concentrations of ligand in a variety of cell lines. Following ligand addi
tion, they translocate to the nucleus, activate p53 inducible genes and ind
uce apoptosis. We have established human head and neck squamous cell carcin
oma lines that stably express LICTS, which are inducible. These lines form
tumours in nude mice in the absence of ligand. Addition of ligand inhibits
tumour formation, and moreover, regresses established tumours by apoptosis.
Although regulatable p53 expression has been achieved previously, our stud
y provides the first demonstration of regulatable in vivo regression of tum
ours in a p53 based approach. Regulated inhibition and regression of tumour
s with a ligand inducible chimeric tumour suppressor could provide a novel
approach to p53 based gene therapy.