Multiple mechanisms of regulation of the human c-myb gene during myelomonocytic differentiation.
Alterations in expression of c-myb can have profound effects on the growth and differentiation of hematopoietic cells. Thus, it is important to understand the mechanisms by which c-myb is regulated during hematopoietic cell differentiation. Previous studies pertaining to the regulation of c-myb have been carried out with the avian and murine forms of the gene; the current studies were designed to determine the mechanisms of regulation of the human form of c-myb. Transcriptional analysis by nuclear run-on assays revealed that an attenuation of transcription was the means of primary regulation during retinoic acid- and vitamin D3-induced differentiation of HL-60 cells, while other mechanisms in addition to attenuation were active during dimethyl sulfoxide (DMSO)- and phorbol ester-induced differentiation. Densitometric analysis of the changes in c-myb transcription caused by phorbol ester suggested that the c-myb promoter may be down-regulated during phorbol ester-induced differentiation of HL-60. Additional studies exhibited post-transcriptional regulation by phorbol ester. DMSO was also shown to regulate c-myb at the post-transcriptional level. Interestingly, the post-transcriptional regulation of c-myb by DMSO required continuous transcription. This requirement was shared for c-myc but not ornithine decarboxylase expression. The transcriptional dependency of c-myb post-transcriptional regulation did not equate to translational dependency, thus a novel post-transcriptional regulatory mechanism may control c-myb gene expression. The multiple levels of regulation of c-myb suggest the importance of proper control for hematopoietic cell differentiation.
Boise
L H
LH
Department of Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Gorse
K M
KM
Westin
E H
EH
D002454:Cell Differentiation; D002762:Cholecalciferol / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020598:Proto-Oncogene Proteins c-myb; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger; D002762:Cholecalciferol; D015240:Phorbol 12,13-Dibutyrate; D014212:Tretinoin; D004121:Dimethyl Sulfoxide