Superoxide induced inhibition of death receptor signaling is mediated via induced expression of apoptosis inhibitory protein cFLIP.

The death inhibitory proteins, cFLIP and Bcl-2, canonically act at different steps to regulate receptor-mediated apoptosis in cancer cells. Here we report that pharmacological or genetic means to effect an increase in intracellular superoxide result in cFLIP upregulation. Interestingly, Bcl-2 overexpression is associated with a concomitant increase in cFLIP, and reducing superoxide sensitizes Bcl-2 overexpressing cancer cells to receptor-mediated apoptosis via downregulation of cFLIP.

FLIP: a flop for execution signals.

Resistance to apoptosis is one of the established hallmarks of cancer cells. This is a function of an imbalance between the proteins that facilitate death execution and those that inhibit apoptosis or promote cell proliferation. The anti-apoptotic protein, FLICE inhibitory protein (FLIP), first identified as a viral protein, is over-expressed in a variety of human pathologies.

The 3'-untranslated region length and AU-rich RNA location modulate RNA-protein interaction and translational control of β2-adrenergic receptor mRNA.

Posttranscriptional controls play a major role in β(2)-adrenergic receptor (β(2)-AR) expression. We recently reported that β(2)-AR mRNA translation is suppressed by elements in its 3'-untranslated region (UTR). We also identified T-cell-restricted intracellular antigen-related protein (TIAR) and HuR as prominent AU-rich (ARE) RNA-binding proteins that associate with β(2)-AR mRNA 3'-UTR.

Transcriptional down-regulation of IGFBP-3 in human hepatocellular carcinoma cells is mediated by the binding of TIA-1 to its AT-rich element in the 3'-untranslated region.

Insulin-like growth factor binding protein-3 (IGFBP-3) plays key roles in regulating cell growth, differentiation, and apoptosis in a variety of cellular systems. We have observed significant down-regulation of IGFBP-3 expression in primary human hepatocellular carcinoma (HCC) tissues when compared to adjacent histologically normal tissues. In this study, we functionally mapped the entire 3'-UTR of the IGFBP-3 mRNA, spanning 1471 nt and identified a 210 bp fragment consisting of AT-rich elements at the distal downstream region preceding the consensus pre-mRNA polyadenylation signal that provide high affinity binding for TIA-1 to mediate the specific suppression of IGFBP-3 expression in human HCC cells.

Translational control of beta2-adrenergic receptor mRNA by T-cell-restricted intracellular antigen-related protein.

Cellular expression of the beta(2)-adrenergic receptor (beta(2)-AR) is suppressed at the translational level by 3'-untranslated region (UTR) sequences. To test the possible role of 3'-UTR-binding proteins in translational suppression of beta(2)-AR mRNA, we expressed the full-length 3'-UTR or the adenylate/uridylate-rich (A+U-rich element (ARE)) RNA from the 3'-UTR sequences of beta(2)-AR in cell lines that endogenously express this receptor. Reversal of beta(2)-adrenergic receptor translational repression by retroviral expression of 3'-UTR sequences suggested that ARE RNA-binding proteins are involved in translational suppression of beta(2)-adrenergic receptor expression.

The 3'-untranslated region of the beta2-adrenergic receptor mRNA regulates receptor synthesis.

beta(2)-Adrenergic receptors (beta(2)-ARs) are low abundance integral membrane proteins that mediate the effects of catecholamines at the cell surface. Post-transcriptional regulation of beta(2)-AR is dependent, in part, on sequences within the 5'- and 3'-untranslated regions (UTRs) of the receptor mRNA. In this work, we demonstrate that 3'-UTR sequences regulate the translation of the receptor mRNA.