Regulation of Primary Response Genes in B Cells

• Published in: The Journal of biological chemistry Vol. 288; no. 21; pp. 14906 - 14916
• Main Authors: Fowler, Trent, Suh, Hyunsuk, Buratowski, Stephen, Roy, Ananda L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.05.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; B Cells; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; c-fos; Cell Line, Tumor; Early Growth Response Protein 2 - biosynthesis; Early Growth Response Protein 2 - genetics; Fos; Gene Expression Regulation - physiology; Gene Regulation; Immunology; Male; Mice; Mitosis - physiology; Proto-Oncogene Proteins c-fyn - biosynthesis; Proto-Oncogene Proteins c-fyn - genetics; RNA Precursors - biosynthesis; RNA Precursors - genetics; RNA Splicing - physiology; Signal Transduction - physiology; Signaling; Spliceosome; Splicing; Time Factors; Transcription; Signaling; Spliceosome; Immunology; Transcription; Splicing; B Cells; c-fos; Fos
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.454355

Deregulated gene expression in B cells often results in various lymphoid malignancies and immune deficiencies. Therefore, understanding signal-induced gene regulatory pathways involved during B cell activation is important to tackle pathologies associated with altered B cell function. Primary response genes (PRGs) are rapidly induced upon signaling in B cells and other cell types and often encode oncogenic transcription factors, which are associated with various malignancies. However, an important issue that remains unclear is whether the fundamental mechanism of activation of these genes is essentially the same under such diverse conditions. c-fos is a PRG that is induced rapidly upon activation of B cells in response to a wide variety of stimuli. Using the c-fos gene as a candidate PRG, we addressed here how it is regulated in response to tumor-promoting and antigen-mimicking signals. Our results show that although the mRNA was induced and extinguished within minutes in response to both signals, surprisingly, apparently full-length unspliced pre-mRNA persisted for several hours in both cases. However, although the mitogenic signal resulted in a more sustained mRNA response that persisted for 4 h, antigenic signaling resulted in a more robust but very transient response that lasted for <1 h. Moreover, the pre-mRNA profile exhibited significant differences between the two signals. Additionally, the splicing regulation was also observed with egr-2, but not with c-myc. Together, these results suggest a previously underappreciated regulatory step in PRG expression in B cells. Background: Primary response genes (PRGs) are important for proliferation and play a prominent role in B cell activation. Results: Distinct stimuli produce distinct modes of PRG regulation at the levels of both splicing and transcription. Conclusion: RNA maturation and splicing are regulated in a signal-specific manner. Significance: The nature of signaling controls the duration of transcriptional and splicing responses.