Muhammad MANSHA, Muhammad WASIM, Ali Raza AWAN, Asma Abdul LATIF

Analysis of Bimbam , a novel glucocorticoid-induced BH3-only transcript in cell lines and children with acute lymphoblastic leukemia

Glucocorticoids (GCs) induce apoptosis and cell cycle arrest in lymphoid cells and are fundamental components of therapeutic regimens of acute lymphoblastic leukemia (ALL). We previously identified a panel of GC-induced candidate genes in children with ALL and in other biological systems using whole genome expression profiling. Of those, a novel transcript from the BCL2L11/Bim locus, named "Bimbam", was functionally analyzed in the current study. The postulated Bimbam mRNA consists of the 5' portion of Bim including the BH3-containing exon 8 and the 3' portion of Bam, a small 2-exon gene embedded in the BCL2L11/Bim locus. The expression and GC induction of Bimbam were similar to those of the combined Bim transcripts in ALL cell lines. The functional analysis with recombinant Bimbam constructs reflected that it induced massive apoptosis on its own and its killing capacity is similar to that of Bim. The localization data indicated that contrary to Bim, which localized preferentially to mitochondria via its C-terminal domain, Bimbam localized to mitochondria and also to other intracytoplasmic membranes. Therefore, it may be responsible for some of the effects previously ascribed to the known Bim transcripts irrespective of the fact that its C-terminus is absolutely different than Bim's C-terminus.

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