Regulation of expression of C-MYC and other growth-related genes during the DNA synthetic response of murine lymphocytes
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Abstract
The regulation of lymphocyte proliferation is important in modulating the immune response. Stimulation of B lymphocyte proliferation requires the presence of specific antigen and growth factors; these requirements can be fullfilled by goat anti-mouse immunoglobulin antibody (GaMig) and cytochalasin D (CD) , an agent that disrupts actin filaments . The effects of this two- signal stimulation on gene expression of c -myc, 8 -actin and 2Fl (a mitochondrial ADP/ATP t ranslocase) was examined. For the 2Fl and c -myc genes, neither GaMig nor CD alone caused a prolonged increase in mRNA levels in B lymphocytes, whereas GaMig plus CD caused a sustained elevation in mRNA levels. Pretreatment with GaMig rendered expression of the c -myc and 2Fl genes susceptible to subsequent action by CD. In contrast , CD alone was sufficient to produce changes in 8- actin gene expression. For c-myc, a major site of regulation occurs at the level of transcription. The combination of GaMig and CD affected both initiation and elongation controls of transcription, whereas either agent alone acted upon initiation . Thus, GaMig a nd CD acted in synergy to induce expression of the c -myc and 2Fl genes, and these effects correlated with the progression of B lymphocytes to DNA synthesis. Another aspect of this thesis was concerned with the decrease with age in mitogenic responsiveness of murine splenic T lymphocytes. The expression of c -myc mRNA was analyzed in concanavalin A (Con A) - stimulated cultures of spleen cells from young and old mice. Aging led to a diminished induction of c -myc mRNA expression by Con A, although the timecourse of induction was unaltered . Further a nalysis i ndicated t hat the decrease in c -myc mRNA expression observed in spleen cells from aged mice is not attributable to alterations in the transcriptional responsiveness or to altered stability of the mature RNA. Thus, an age- associated defect in processing or transport of c -myc RNA may occur.
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Dissertation (Ph.D.)--Boston University
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