cAMP differentially regulates gamma-globin gene expression in erythroleukemic cells and primary erythroblasts through c-Myb expression.
Our previous studies demonstrated roles of cyclic nucleotides in gamma-globin gene expression. We recently found that, upon activation of the cAMP pathway, expression of the gamma-globin gene is inhibited in K562 cells but induced in adult erythroblasts. Here we show that c-Myb, a proto-oncogene product that plays a role in cell growth and differentiation, is involved in the cAMP-mediated differential regulation of gamma-globin gene expression in K562 cells and primary erythroblasts. Our studies found that c-Myb is expressed at a high level in K562 cells compared to primary erythroblasts, and that c-Myb expression is further increased following the treatment with forskolin, an adenylate cyclase activator. The induction of gamma-globin gene expression was also inhibited in K562 cells by raising the levels of c-Myb expression. Importantly, forskolin-induced erythroid differentiation in K562 cells, as determined by the expression of glycophorins and CD71, suggesting that high-level expression of c-Myb may not be sufficient to inhibit the differentiation of erythroid cells. In contrast, c-Myb was not expressed in adult erythroblasts treated with forskolin and primary erythroblasts may lack the c-Myb-mediated inhibitory mechanism for gamma-globin gene expression. Together, these results show that the cAMP pathway blocks gamma-globin gene expression in K562 cells by increasing c-Myb expression and c-Myb plays a role in defining the mode of response of the gamma-globin gene to fetal hemoglobin inducers in erythroid cells.
Kuroyanagi
Yuichi
Y
Institute of Molecular Medicine and Genetics, Department of Medicine, Medical College of Georgia, Augusta, GA 30912, USA.
Kaneko
Yuji
Y
Muta
Kenjiro
K
Park
Buem-Seek
BS
Moi
Paolo
P
Ausenda
Sabrina
S
Cappellini
Maria D
MD
Ikuta
Tohru
T
D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D004900:Erythroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D005914:Globins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; D005914:Globins; D000242:Cyclic AMP