bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.

Abstract

SummaryWe have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xr, a product of bd-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xr but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xt within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-x t are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-XL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.

Role of the translocation partner in protection against AID-dependent chromosomal translocations

“…To determine whether persistent activation of Bcl-2 or Bcl-XL is sufficient to protect against c-myc/IgH translocation, we analyzed activated B cells from Bcl-2 and Bcl-XL transgenic mice (46,47). Consistent with their prosurvival function, deregulated expression of Bcl-2 or Bcl-XL increased the number of live cells that failed to divide or underwent a small number of cell divisions in response to LPS + IL4 ( Fig.…”

“…The surprising difference between Bcl-XL and Bcl-2 might in part be attributed to a reciprocal expression pattern of these two factors in developing and activated B cells. Whereas Bcl-XL is expressed in pre-B cells, Bcl-2 is expressed in and is crucial for the survival of immature and mature naïve B cells (47,73), and only Bcl-XL is significantly up-regulated in activated B cells (47). Thus, enforced transgenic expression of Bcl-2 under the control of Ig regulatory elements in the Bcl-2 transgene may account in part for its interference with CSR and inability to protect against accumulation of cells with c-myc/IgH translocation.…”

t(14;18), a journey to eternity

“…52 In contrast, the bcl-2 homologous gene bcl-xl becomes up-regulated during the pre-B cell stage. 53 Downand up-regulation of Bcl-2 and Bcl-xl may coincide with several selection processes. First, selection for functional rearrangements of IgH and IgL loci may coincide with downregulation of Bcl-2 and up-regulation of Bcl-xl.…”

“…48,54 In vitro stimuli like ␣IgM, ␣CD23 plus rIL-1␣, ␣CD40 or CD40-ligand, which mimic in vitro selection stimuli induce BCL2 and BCL-X L up-regulation in centrocytes of splenic B cells. 53,55 …”

Syk Interacts with and Phosphorylates Nucleolin To Stabilize Bcl-xL mRNA and Promote Cell Survival

“…This interaction protects cells from the loss of Bcl-x L resulting from exposure to inducers of oxidative or genotoxic stress. It is of interest to note that both Syk and Bcl-x L are important prosurvival factors in pre-B cells that have undergone gene rearrangements necessary for expression of a pre-B-cell antigen receptor, an event essential for B-cell survival in vivo (56,57). Bcl-x L is also elevated in germinal center B cells undergoing class switching and somatic hypermutation (58), conditions under which DNA strand breaks are likely to occur (and which are events also induced in cells treated with doxorubicin or etoposide).…”