title: Modulation of Ets-1 expression in B lymphocytes is dependent on the antigen receptor-mediated activation signals and cell cycle status.
abstract: In this report, we tested the hypothesis that Ets-1 transcription factor is modulated at the mRNA level during B cell antigen receptor (BCR)-induced cell-signalling events. Quiescent B cells express high levels of Ets-1 mRNA. Stimulation through the BCR results in time-dependent inhibition of Ets-1 mRNA expression in primary splenic B cells with maximal inhibition observed by 16-h post-stimulation. Inhibition of Ets-1 expression is specific to antigen receptor but not CD40-mediated activation. Antigen receptor-induced inhibition of Ets-1 mRNA can be mimicked by phorbol myristate acetate (PMA) and/or ionomycin. PMA but not ionomycin-induced inhibition of Ets-1 expression is rescued by the inhibitors of protein kinase C and MEK. Extended time-course analysis revealed a time-dependent cyclical pattern in the re-expression of Ets-1 mRNA. While resting cells revealed maximal Ets-1 mRNA expression, activation events that induced exit from G(0) /G(1)  or cells blocked in early S phase exhibited decreased Ets-1 mRNA levels. Interestingly, cells arrested at late G2 or M phase of the cell cycle failed to down modulate Ets-1 mRNA expression. Overexpression of Ets-1 in 70Z/3 B cell line caused abnormal accumulation of cells in S phase associated with increased cyclin A expression. Consistent with a requirement for Ets-1 in BCR-induced cell cycle entry, splenic B cells from mice deficient in Ets-1 showed defective antigen receptor-induced DNA synthesis and S phase entry. These results suggest a critical role for Ets-1 regulation during B cell activation and cell cycle entry.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Raghunandan
authors.forename: F W
authors.initials: FW
authors.lastname: Frissora
authors.forename: N
authors.initials: N
authors.lastname: Muthusamy
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D008213:Lymphocyte Activation; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019925:Cyclin A; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D011493:Protein Kinase C; D002118:Calcium