We have analyzed immunoglobulin light chain sequences from avian leukosis virus (ALV) induced bursal and metastatic tumors and from cell lines derived from these tumors. Sequence data presented demonstrate that ALV‐induced tumors and one cell line (DT40) derived therefrom continue to diversify their light chain genes outside of the bursal environment. Diversification within these tumor cells seems to occur by gene conversion events comparable with those observed in bursal B cells. Sequence analysis of spontaneously arising surface immunoglobulin negative subclones of the DT40 cell line revealed frameshifts within the rearranged light chain genes which most likely resulted from non‐functional recombination events. Superimposed gene conversion events can repair these frameshifts leading to re‐expression of surface immunoglobulin.
Cell-substratum adhesion is an essential requirement for survival of human neonatal keratinocytes in vitro. Similarly, activation of the epidermal growth factor receptor (EGF-R) has recently been implicated not only in cell cycle progression but also in survival of normal keratinocytes. The mechanisms by which either cell-substratum adhesion or EGF-R activation protect keratinocytes from programmed cell death are poorly understood. Here we describe that blockade of the EGF-R and inhibition of substratum adhesion share a common downstream event, the down-regulation of the cell death protector Bcl-x L . Expression of Bcl-x L protein was down-regulated during forced suspension culture of keratinocytes, concurrent with large-scale apoptosis. Similarly, EGF-R blockade was accompanied by down-regulation of Bcl-x L steady-state mRNA and protein levels to an extent comparable to that observed in forced suspension culture. However, down-regulation of Bcl-x L expression by EGF-R blockade was not accompanied by apoptosis; in this case, a second signal, generated by passaging, was required to induce rapid and large-scale apoptosis. These findings are consistent with the conclusions that (i) Bcl-x L represents a shared molecular target for signaling through cell-substrate adhesion receptors and the EGF-R, and (ii) reduced levels of Bcl-x L expression through EGF-R blockade lower the tolerance of keratinocytes for cell death signals generated by cellular stress.
The expression of human bcl-2 gene is de-regulated by t(14;18) translocation in most of follicular lymphoma. Recent studies indicated that the bcl-2 gene product has an ability to block apoptosis of hematopoietic cells. To facilitate the analysis of the role of this gene in normal development using an animal model, we have isolated and partially characterized the chicken homologue of human bcl-2 gene. The analysis of nucleotide sequence showed that the organization of the chicken bcl-2 gene is very similar to that of human bcl-2 gene. The primary transcript is spliced to encode a 25,687 dalton (233 a.a.) protein. The chicken Bcl-2 protein has two regions highly homologous to human Bcl-2 protein surrounding a totally non-homologous region. The expression of the chicken bcl-2 gene was analyzed in various chicken tissues. In the adult chicken, bcl-2 transcripts were detected in thymus, spleen, kidney, heart, ovary and brain, with the highest levels being detected in the thymus. However, the bursa of Fabricius, which is the site of early B cell development, expressed much less amounts of bcl-2 RNA. On the other hand, in embryo, the gene is extensively expressed in the bursa, as well as in muscle and the above tissues. Our findings indicate that a homologue of the human bcl-2 gene does exist in the chicken and that its expression is developmentally regulated in some tissues.
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