Regulation of BAG-1 IRES-mediated translation following chemotoxic stress

Abstract

There are three major isoforms of BAG-1 in mammalian cells, termed BAG-1L (p50), BAG-1M (p46) and BAG-1S (p36) that function as pro-survival proteins and are associated with tumorigenesis and chemoresistance. Initiation of BAG-1 protein synthesis can occur by both capdependent and cap-independent mechanisms and it has been shown that synthesis of BAG-1S is dependent upon the presence of an internal ribosome entry segment (IRES) in the 5 0 -UTR of BAG-1 mRNA. We have shown previously that BAG-1 IRES-meditated initiation of translation requires two trans-acting factors poly (rC) binding protein 1 (PCBP1) and polypyrimidine tract binding protein (PTB) for function. The former protein allows BAG-1 IRES RNA to attain a structure that permits binding of the ribosome, while the latter protein appears to be involved in ribosome recruitment. Here, we show that the BAG-1 IRES maintains synthesis of BAG-1 protein following exposure of cells to the chemotoxic drug vincristine but not to cisplatin and that this is brought about, in part, by the relocalization of PTB and PCBP1 from the nucleus to the cytoplasm.

For IRES trans-acting factors, it is all about location

“…In fact, it is entirely possible that the inappropriate subcellular distribution of ITAFs contributes to the dysregulation of IRES-dependent translation during disease and pathophysiological conditions. This suggestion is highlighted by the fact that Dobbyn et al (2007) find that treatment of cells with the chemotoxic drug vincristine in fact increases the relative abundance of the antiapoptotic factor BAG-1S due to reinforced IRESmediated translation caused by the vincristine-induced subcellular relocalization of PTB and PCBP1. Thus, cells that should succumb to vincristine treatment are instead resistant to the drug due to enhanced IRESdependent translation of an antiapoptotic factor.…”

“…Exactly how ITAFs enable IRES-dependent translation, and how the activities of these proteins themselves are regulated, is an active field of investigation. A new report from Dobbyn et al (2007) (this issue) and other recent findings (Lewis et al, 2007;Lin et al, 2007) suggest that the activity of ITAFs in IRES-dependent translation initiation is regulated by the subcellular distribution of these proteins. Dobbyn et al (2007) were studying how translation of the prosurvival protein BAG-1 is regulated during chemotoxic stress, with a particular focus on the BAG-1S isoform whose translation is mediated by an IRES.…”

“…A new report from Dobbyn et al (2007) (this issue) and other recent findings (Lewis et al, 2007;Lin et al, 2007) suggest that the activity of ITAFs in IRES-dependent translation initiation is regulated by the subcellular distribution of these proteins. Dobbyn et al (2007) were studying how translation of the prosurvival protein BAG-1 is regulated during chemotoxic stress, with a particular focus on the BAG-1S isoform whose translation is mediated by an IRES. The authors found that although treatment with the chemotoxic drug vincristine represses global, capdependent translation initiation, the IRES-dependent translation of BAG-1S is refractory to such treatment.…”

La Autoantigen Mediates Oxidant Induced De Novo Nrf2 Protein Translation

“…Alternatively, these ITAFs are confined in the nucleus until appropriate signals are received (38). For example, in HeLa cells treated with vincristine, translation of the antiapoptotic protein BAG1 increases through an IRES mediated mechanism (39). PTB and PCBP1 as ITAFs of BAG1 translocate from the nuclei to the cytoplasm upon vincristine treatment.…”

Bag-1L is a Stress-withstand Molecule Prevents the Downregulation of Mcl-1 and c-Raf Under Control of Heat Shock Proteins in Cisplatin Treated HeLa Cervix Cancer Cells

“…In addition, overexpression of Bag-1 promotes cell survival and differentiation via interacting Bcl-2, an antiapoptotic protein. It is hypothesized that Bag-1 binds to Hsp/Hsc70-substrate complexes to regulate the potential substrates of this complex such as Bcl-2, Raf, NHRs (Wang et al, 1996;Wang and Reed 1998;Dobbyn et al, 2008). In order to assess the potential role of Bag-1 in drug-induced apoptosis mechanism, we questioned the role of several key players in cellular cell death and survival decision.…”