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cAMP-induced NF-kappaB (p50/relB) binding to a c-myb intronic enhancer correlates with c-myb up-regulation and inhibition of erythroleukemia cell differentiation.

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.
AuthorsM Suhasini, C D Reddy, E P Reddy, J A DiDonato, R B Pilz
JournalOncogene (Oncogene) Vol. 15 Issue 15 Pg. 1859-70 (Oct 09 1997) ISSN: 0950-9232 [Print] England
PMID9362453 (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

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