The goal of this grant and its three predecessors is to understand molecular events related to Ig heavy chain gene expression. Alternative 3' end selection is the rate-limiting step for the biosynthesis of mu and delta mRNAs and there membrane (m) and secreted (s) forms. In the last period, we showed that the geometry of the Cmu-Cdelta transcription unit and the spacing strength, and downstream sequences associated with mu s and mu m poly(A) sites were major contributors. Consequent to this regulation and critical to subsequent transmembrane signaling, expression of the mIg antigen receptor is achieved. Through mutagenesis of antigen-specific transfectants we have defined differential roles for the mIg carboxyl-terminus in this process.
Aim 1 seeks to continue studies on mu s/mu m regulation and on the function of mIg as an antigen receptor in immediate, late and differentiative events.
Aim 2 intends to characterize two categories of B cell-specific proteins, potentially regulatory for the membrane-secretory developmental shift. These are a VH-promoter binding factor induced by lymphokines or LPS, and a family of putative DNA-binding proteins assessed only at the secretory B cell stage. We recently discovered that the JH-Cmu intronic enhancer (Emu) contains an origin of DNA replication preferentially active in B cells.
Aim 3 will further define the sequences involved and how Emu may coordinate transcription and replication timing.
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