Induction of transformed cells to terminal differentiation.

HMBA induces MEL cells to terminal erythroid differentiation. HMBA causes a decrease in diacylglycerol concentration, a decrease in Ca+2 and phospholipid-dependent protein kinase C activity (within 2 hr). There is an early (within 1-2 hrs) suppression of c-myb and c-myc gene transcription and an increase in c-fos mRNA (within 4 hrs). During the early or "latent" period there is no detectable commitment of MELC to terminal cell division or expression of differentiated genes such as alpha 1 or beta maj globin genes. HMBA-induced commitment to terminal differentiation is detected by 12 hrs and over 95% become committed cells by 48-60 hrs. Commitment is associated with persistent suppression of c-myb gene transcription and elevated levels of c-fos mRNA, whereas the level of c-myc mRNA returns to that of uninduced cells. By 36-48 hrs, transcription of the alpha 1 and beta maj globin genes increases 10-30 fold, and that of rRNA genes is suppressed. Changes in expression of c-myb, c-myc, c-fos and p53 genes that occur early during HMBA-induced differentiation may be important in the multistep process involved in commitment of MEL cells to terminal differentiation. Continued suppression of c-myb gene expression may be required for terminal differentiation of these cells.