Effects of selective down-modulation of Insulinoma glucagonoma 20 splice variants on cancer cell survival.

Effects of selective down-modulation of Insulinoma glucagonoma 20 splice variants on cancer cell survival

Resistance to TRAIL-induced apoptosis: role of IG20 splice variants

Tumor necrosis factor receptor–related apoptosis-inducing ligand (TRAIL) can induce apoptosis primarily in cancer cells with little or no effect on normal cells; therefore, it has the potential for use in cancer therapy. TRAIL binding to death receptors DR4 and DR5 triggers the death-inducing signal complex formation and activation of procaspase-8, which in turn activates caspase-3, leading to cell death. Like FasL, TRAIL can trigger type 1 (caspase-8 caspase-3) or type 2 (caspase-8 Bid cleavage capsase-9 caspase-3) apoptotic pathways depending on the cell type. Some cancers are resistant to TRAIL treatment because most molecules in the TRAIL signaling pathway, including FLIPs and IAPs, can contribute to resistance. In addition, we have identified an essential role for splice variants of the IG20 gene in TRAIL resistance

Regulation of Apoptosis and Caspase-8 Expression in Neuroblastoma Cells by Isoforms of the IG20

Pavilion of Ten Thousand Autumns (Qian Qiu Ting) in the west garden; The Forbidden City was the Chinese imperial palace from the Ming Dynasty to the end of the Qing Dynasty. To the west of the Inner Palace is the residential quarter of the Qing emperors, with numerous smaller buildings and gardens. To the east stood the residence of the imperial concubines and various ritual halls, as well as theatres, temples and gardens. Source: Wikipedia; http://en.wikipedia.org/wiki/Main_Page (accessed 5/11/2011

MADD, a Splice Variant of IG20, Is Indispensable for MAPK Activation and Protection against Apoptosis upon Tumor Necrosis Factor-α Treatment*

We investigated the physiological role of endogenous MAPK-activating death domain-containing protein (MADD), a splice variant of the IG20 gene, that can interact with TNFR1 in tumor necrosis factor-α (TNFα)-induced activation of NF-κB, MAPK, ERK1/2, JNK, and p38. Using exon-specific short hairpin RNAs expressing lentiviruses, we knocked down the expression of all IG20 splice variants or MADD, which is overexpressed in cancer cells. Abrogation of MADD expression rendered cells highly susceptible to TNFα-induced apoptosis in the absence of cycloheximide. It also resulted in a dramatic loss in TNFα-induced activation of MAPK without any apparent effect on NF-κB activation. This observation was substantiated by an accompanying loss in the activation of p90RSK, a key downstream target of MAPK, whereas the NF-κB-regulated interleukin 6 levels remained unaffected. Endogenous MADD knockdown, however, did not affect epidermal growth factor-induced MAPK activation thereby demonstrating the specific requirement of MADD for TNF receptor-mediated MAPK activation. Re-expression of short hairpin RNA-resistant MADD in the absence of endogenous IG20 expression rescued the cells from TNFα-induced apoptosis. The requirement for MADD was highly specific for TNFα-induced activation of MAPK but not the related JNK and p38 kinases. Loss of MADD expression resulted in reduced Grb2 and Sos1/2 recruitment to the TNFR1 complex and decreased Ras and MEKK1/2 activation. These results demonstrate the essential role of MADD in protecting cancer cells from TNFα-induced apoptosis by specifically activating MAPKs through Grb2 and Sos1/2 recruitment, and its potential as a novel cancer therapeutic target

Endocytic Pathways Involved in Filovirus Entry: Advances, Implications and Future Directions

Detailed knowledge of the host-virus interactions that accompany filovirus entry into cells is expected to identify determinants of viral virulence and host range, and to yield targets for the development of antiviral therapeutics. While it is generally agreed that filovirus entry into the host cytoplasm requires viral internalization into acidic endosomal compartments and proteolytic cleavage of the envelope glycoprotein by endo/lysosomal cysteine proteases, our understanding of the specific endocytic pathways co-opted by filoviruses remains limited. This review addresses the current knowledge on cellular endocytic pathways implicated in filovirus entry, highlights the consensus as well as controversies, and discusses important remaining questions