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.
Marks
P A
PA
DeWitt Wallace Research Laboratories, Memorial Sloan-Kettering Cancer Center, New York, New York.
Sheffery
M
M
Ramsay
R
R
Ikeda
K
K
Rifkind
R A
RA
D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002472:Cell Transformation, Viral; D004275:DNA, Ribosomal / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D011519:Proto-Oncogenes; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D000081:Acetamides; D004275:DNA, Ribosomal; D011518:Proto-Oncogene Proteins; D005914:Globins; C014026:hexamethylene bisacetamide