Herbimycin A down-regulates messages of cyclin D1 and c-myc during erythroid differentiation of K562 cells.
The ansamycin antibiotic, herbimycin A, is a potent tyrosine kinase inhibitor, and induces the erythroid differentiation of bcr-abl-possessing K562 cells. The growth of K562 cells was cytostatically reduced to less than 50% of the control level at 48 h by 0.5 microgram/ml of herbimycin A treatment. A total of 12% and 53% of the treated cells were benzidine-positive at 24 h and 48 h, respectively. The percentage of cells in the S phase decreased rapidly from 60% to 15% after 12 h of treatment. The reduction of S phase cells persisted until 24 h, whereas the G1 population conversely increased. Then underphosphorylated retinoblastoma gene product increased from 6 h to 24 h, but returned to baseline at 48 h. Most cell cycle controlling genes were unchanged by herbimycin A treatment. However, both cyclin D1 and c-myc were prominently down-regulated in the early phase of treatment, corresponding to the decline of the S phase population. Cyclin D1 was initially down-regulated to an undetectable level at 6 h, although its expression recovered gradually from 12 h and returned to baseline at 24 h. c-myc was also down-regulated from 1 h to 6 h. These data suggest that signals originating from bcr-abl kinase are at least partly transduced through both c-myc and cyclin D1, and that herbimycin A-induced erythroid differentiation occurs during or after the cessation of growth due to interference with these signals.
Yamada
H
H
Jikei University, School of Medicine, Aoto Hospital, Department of Internal Medicine, Tokyo, Japan.
Iwase
S
S
Nagai
M
M
Nemoto
T
T
Sekikawa
T
T
Takahara
S
S
Nakada
S
S
Furukawa
Y
Y
Horiguchi-Yamada
J
J
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones; D002454:Cell Differentiation / Q000187:drug effects; D019938:Cyclin D1; D016213:Cyclins / Q000235:genetics*; D015536:Down-Regulation; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011809:Quinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects*; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D016213:Cyclins; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D011809:Quinones; D012333:RNA, Messenger; D019938:Cyclin D1; D017828:Rifabutin; C020754:herbimycin