Posttranscriptional regulation of gene expression of mRNAs containing adenine-uridine rich elements (AREs) in their 3′ untranslated regions is mediated by a number of different proteins that interact with these elements to either stabilise or destabilise them. The present review concerns the TPA-inducible sequence 11 (TIS11) protein family, a small family of proteins, that appears to interact with ARE-containing mRNAs and promote their degradation. This family of proteins has been extensively studied in the past decade. Studies have focussed on determining their biochemical functions, identifying their target mRNAs, and determining their roles in cell functions and diseases.
SummaryChronic lymphocytic leukaemia cells survive and proliferate in patients but rapidly die in culture. The microenvironment that sustains leukaemic cells in vivo contains both stromal cell elements and T cells. We defined changes in Bcl-2 family protein expression on culture with CD40 ligand (CD154) expressed on mouse fibroblast L cells, and interleukin-4 (IL-4; CD154/IL-4 system): conditions that support survival and proliferation. Unexpectedly, Bcl-2 protein expression decreased whilst pro-survival Bcl-x L (as well as A1 and Mcl-1) increased. However, the CD154-L cell/IL-4 system also increased the pro-apoptotic proteins, Bid and Noxa, suggesting that an increased pool of pro-survival factors and not the effects of a single protein mediate survival. Most pro-apoptotic proteins were not induced in drug or spontaneous apoptosis, but expression of Bcl-x S , a pro-apoptotic BCL2L1 isoform, was associated with cell death. This was post-transcriptionally controlled, and, therefore, alternative splicing at the Bcl-x locus appears to have a role in the regulation of chronic lymphocytic leukaemia (CLL) cell survival. This study demonstrated a switch in pro-survival proteins associated with the transition from quiescence to CD154-driven proliferation. CLL therapies targeting Bcl-2 may need to be modified to antagonize proliferation centre-specific prosurvival proteins.
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