Developmental regulation of the Bcl-2 protein and susceptibility to cell death in B lymphocytes.

Abstract

Cell death is a prominent feature of B cell development. For example, a large population of B cells dies at the pre‐B cell stage presumably due to the failure to express a functional immunoglobulin receptor. In addition, developing B cells expressing antigen receptors for self are selectively eliminated at the immature B cell stage. The molecular signals that control B cell survival are largely unknown. The product of the bcl‐2 proto‐oncogene may be involved as its overexpression inhibits apoptotic cell death in a variety of biological systems. However, the physiological role of the endogenous Bcl‐2 protein during B cell development is undetermined. Here we show a striking developmental regulation of the Bcl‐2 protein in B lymphocytes. Bcl‐2 is highly expressed in CD43+ B cell precursors (pro‐B cells) and mature B cells but downregulated at the pre‐B and immature B cell stages of development. We found that Bcl‐2 expressed by B cells is a long‐lived protein with a half‐life of approximately 10 h. Importantly, susceptibility to apoptosis mediated by the glucocorticoid hormone dexamethasone is stage‐dependent in developing B cells and correlates with the levels of Bcl‐2 protein. Furthermore, expression of a bcl‐2 transgene rescued pre‐B and immature B cells from dexamethasone‐induced cell death, indicating that Bcl‐2 can inhibit the apoptotic cell death of progenitors and early B cells. Taken together, these findings argue that Bcl‐2 is a physiological signal controlling cell death during B cell development.

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

“…It is therefore possible that cleaved Bfl-1 readily manifests its proapoptotic phenotype because its half-life is fairly short (o2 h for 2xMyc-Bfl-1) compared to that of Bcl-2 (B10 h). 57,58 Although the cleavage site(s) in Bfl-1 remain(s) to be mapped precisely, our studies raise the possibility that Bfl-1 might be converted into a proapoptotic Bax-like multi-BH1-3 protein. For example, cleavage of Bcl-2 and Bcl-xL by caspases or calpain generates a Bax-like fragment, and the proapoptotic activity of Bcl-2-derived fragment was shown to depend on the integrity of the BH3 and TM domains.…”

t(14;18), a journey to eternity

“…49,50 Although bcl-2 seems not to be absolutely required for embryonal development, it is essential for long-term survival and maintenance of at least some cell types. 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.…”

Tissue-selective therapy of cancer

“…Even during physiological stress, glucorticoids can kill CD4( þ ) and CD8( þ ) thymocytes (Ashwell et al, 2000). In addition to T lymphocytes, glucocorticoids induce apoptosis in B cells, pre-B and immature B cells, which is inhibited by Bcl-2 (Merino et al, 1994). Bcl-2 is highly expressed in B-cell precursors (pro-B cells) and mature B cells, but is low at the pre-B and immature B-cell stages of development (Merino et al, 1994).…”

“…In addition to T lymphocytes, glucocorticoids induce apoptosis in B cells, pre-B and immature B cells, which is inhibited by Bcl-2 (Merino et al, 1994). Bcl-2 is highly expressed in B-cell precursors (pro-B cells) and mature B cells, but is low at the pre-B and immature B-cell stages of development (Merino et al, 1994). High levels of Bcl-2 and Bcl-x render intestinal intraepithelial lymphocytes resistant to apoptosis by glucocorticoids (Van Houten et al, 1997).…”