Stimulation of cell division and fibroblast focus formation by antisense repression of retinoblastoma protein synthesis.

Circumstantial evidence supports a role for the retinoblastoma susceptibility gene, Rb-1, in the maintenance of normal cell growth, in that loss of its function results in abnormal growth and malignancy. Here we report that a high rate of mitosis and efficient dense focus formation in human embryonic lung fibroblasts (HEL cells) is induced by antisense oligonucleotide-directed inhibition of synthesis of p105-Rb, the product of the Rb-1 gene. mRNA specific for p105-Rb is truncated at the site of base pairing with the antisense oligonucleotide, and no synthesis of p105-Rb is observed. The rate of mitosis is considerably increased and the frequency of dense focus formation is extremely high in treated cells. However, although phosphothioate oligodeoxyribonucleotides taken up by the cells remain stable for at least 4 weeks, the recipient cells do not become immortal; nor are they able to induce tumor formation in nude mice. Thus, loss of Rb-1 function is not sufficient per se to allow malignant transformation.