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A retraction of the article "Inhibitor of Nrf2 (INrf2 or Keap1) protein degrades Bcl-xL via phosphoglycerate mutase 5 and controls cellular apoptosis," by Suryakant K. Niture and Anil K. Jaiswal in the 2011 issue is presented.

Myofibrillar myopathies (MFM) are caused by mutations in at least 6 Z-disc associated proteins, including ZASP, myotilin, desmin, BAG3, αβ-crystallin, and filamin C. MFM are characterized by early and prominent disruption of the Z-disc with focal dissolution of myofibrils and ectopic accumulation of myofibrillar proteins. Similar morphological changes in skeletal muscle in MFM suggest a shared cellular and molecular disease mechanism. ZASP interacts with myotilin, and knock down of ZASP in mice results in alterations in the amounts of other MFM gene products. We hypothesize that ZASP associations with other MFM gene products play a role in the disease mechanism in zaspopathy. To examine the effects of ZASP mutations on the other MFM gene products in skeletal muscle, WT and mutant (A147T and A165V) ZASP-GFP proteins were expressed by electroporation in the tibialis anterior muscles of opposite limbs in wild type mice (n =18). Muscle tissues were harvested at 1, 2, and 4weeks after the electroporation. The amount and distribution of MFM gene products, F-actin, and α-actinin-2 were examined in the electroporated mouse muscle fibers and in skeletal muscle fibers of patients with zaspopathy. Wild type and mutant ZASP interactions with other MFM gene products were examined by co-IP and pulldown assays. Preliminary data suggests that wild type and mutant ZASP associate with myotilin, desmin, and BAG3. The effects of ZASP mutations on the other MFM gene products and the effects of the other MFM gene defects on ZASP will provide insight into shared disease mechanisms in this group of degenerative myopathies. [Copyright &y& Elsevier]

Myofibrillar myopathies are a group of chronic muscle diseases characterised at the cellular level by failure of the muscle fibre at the Z-disk and accumulation of protein aggregates. The vast majority of these diseases are late onset dominant disorders with symptoms typically evident between 35 and 50years of age. Patients suffer progressive muscle weakness over many years and have reduced life expectancy due to respiratory muscle failure and cardiac complications. Whilst structural failure of the muscle fibre is a feature of myofibrillar myopathies not all of the proteins associated with myofibrillar myopathy have a structural role. Recently mutations in BAG3, a co-chaperone with no direct role in muscle function, were identified as a cause of this disorder. This discovery opened a new area of investigation into the role of chaperones in myopathies and the mechanism of disease in myofibrillar myopathy. In order to investigate the role of BAG3 in muscle development and disease we examined zebrafish lacking BAG3 and those with ectopic expression of GFP-tagged forms of either wildtype BAG3 or the dominant myofibrillar myopathy mutant form Bag3P209L. Examination of these fish identified both the fibre failure and the formation of protein aggregates characteristic of myofibrillar myopathy. Utilising the advantage of the zebrafish model system to examine the onset and progression of the phenotype in vivo, combined with detailed characterisation by immunolabelling and confocal microscopy, we were able to develop a novel model that explains the mechanism of disease in BAG3 related myofibrillar myopathy. We will present this model and discuss its implications for other forms of myofibrillar myopathy. [Copyright &y& Elsevier]

Induction of genes is rarely an isolated event; more typically occurring as part of a web of parallel interactions, or motifs, which act to refine and control gene expression. Here, we define an Incoherent Feed-forward Loop motif in which TNFα-induced NF-κB signalling activates expression of the TNFA gene itself and also controls synthesis of the negative regulator BCL-3. While sharing a common inductive signal, the two genes have distinct temporal expression profiles. Notably, while the TNFA gene promoter is primed to respond immediately to activated NF-κB in the nucleus, induction of BCL3 expression only occurs after a time delay of about 1h. We show that this time delay is defined by remodelling of the BCL3 gene promoter, which is required to activate gene expression, and characterise the chromatin delayed induction of BCL3 expression using mathematical models. The models show how a delay in inhibitor production effectively uncouples the rate of response to inflammatory cues from the final magnitude of inhibition. Hence, within this regulatory motif, a delayed (incoherent) feed-forward loop together with differential rates of TNFA (fast) and BCL3 (slow) mRNA turnover provide robust, pulsatile expression of TNFα . We propose that the structure of the BCL-3-dependent regulatory motif has a beneficial role in modulating expression dynamics and the inflammatory response while minimising the risk of pathological hyper-inflammation. [ABSTRACT FROM AUTHOR]

The prostate cancer antigen gene 3 (PCA3) is embedded in an intron of a second gene BMCC1 (Bcl2-/adenovirus E1B nineteen kDa-interacting protein 2 (BNIP-2) and Cdc42GAP homology BCH motif-containing molecule at the carboxyl terminal region 1) which is also upregulated in prostate cancer. BMCC1 was initially annotated as two genes (C9orf65/PRUNE and BNIPXL) on either side of PCA3 but our data suggest that it represents a single gene coding for a high molecular weight protein. Here we demonstrate for the first time the expression of a >300 kDa BMCC1 protein (BMCC1-1) in prostate cancer and melanoma cell lines. This protein was found exclusively in the microsomal fraction and localised to cytoplasmic vesicles. We also observed expression of BMCC1 protein in prostate cancer sections using immunohistology. GST pull down, immunoprecipitation and mass spectrometry protein interaction studies identified multiple members of the Adaptor Related Complex 2 (AP-2) as BMCC1 interactors. Consistent with a role for BMCC1 as an AP-2 interacting endosomal protein, BMCC1 co-localised with β-adaptin at the perinuclear region of the cell. BMCC1 also showed partial co-localisation with the early endosome small GTP-ase Rab-5 as well as strong co-localisation with internalised pulse-chase labelled transferrin (Tf), providing evidence that BMCC1 is localised to functional endocytic vesicles. BMCC1 knockdown did not affect Tf uptake and AP-2 knockdown did not disperse BMCC1 vesicular distribution, excluding an essential role for BMCC1 in canonical AP-2 mediated endocytic uptake. Instead, we posit a novel role for BMCC1 in post-endocytic trafficking. This study provides fundamental characterisation of the BMCC1 complex in prostate cancer cells and for the first time implicates it in vesicle trafficking. [ABSTRACT FROM AUTHOR]