Abstract |
During hexamethylene bisactamide ( HMBA)-induced differentiation of murine erythroleukemia (MEL) cells erythroid genes are transcriptionally activated while c-myb and several other nuclear proto-oncogenes are down-regulated. Differentiation is inhibited by cAMP analogues and the adenyl cyclase-stimulating agent forskolin. We found that these drugs prevented the late down-regulation of c-myb which is known to be critical for MEL cell differentiation. Since the increase in c-myb mRNA levels was due to increased mRNA transcription, we examined the transcription factors NF-kappaB and AP-1 which have been implicated in the regulation of c-myb expression. Binding of MEL cell nuclear proteins to a NF-kappaB recognition sequence in c-myb intron I was strongly induced by 8-Br-cAMP or forskolin; induction was delayed and correlated with the up-regulation of c-myb. The cAMP-induced NF-kappaB complex contained p50 and RelB; in co-transfection assays, p50 and RelB transactivated a reporter construct containing the c-myb intronic NF-kappaB site upstream of a minimal promoter. 8-Br-cAMP and forskolin also increased the DNA binding activity of AP-1 complexes containing JunB, JunD and c-Fos in MEL cells which could cooperate with NF-kappaB. We conclude that inhibition of MEL cell differentiation by pharmacological doses of cAMP can be explained by the up-regulation of c-myb which is mediated, at least in part, by NF-kappaB p50/RelB heterodimers.
|
Authors | M Suhasini, C D Reddy, E P Reddy, J A DiDonato, R B Pilz |
Journal | Oncogene
(Oncogene)
Vol. 15
Issue 15
Pg. 1859-70
(Oct 09 1997)
ISSN: 0950-9232 [Print] England |
PMID | 9362453
(Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
|
Chemical References |
- NF-kappa B
- RNA, Messenger
- Transcription Factors
- Colforsin
- Cyclic AMP
|
Topics |
- Animals
- Cell Differentiation
(genetics)
- Colforsin
(pharmacology)
- Cyclic AMP
(analogs & derivatives, pharmacology)
- Enhancer Elements, Genetic
- Genes, Reporter
- Introns
- Leukemia, Erythroblastic, Acute
(genetics, metabolism, pathology)
- Mice
- NF-kappa B
(metabolism)
- Oncogenes
- Protein Binding
- RNA, Messenger
(genetics, metabolism)
- Subcellular Fractions
(metabolism)
- Transcription Factors
(metabolism)
- Tumor Cells, Cultured
|