. Differential utilization of upstream AUGs in the beta-secretase mRNA suggests that a shunting mechanism regulates translation. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2794-9. PubMed.

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  1. The Rogers et al. paper (contributed by G.M. Edelman to PNAS) describes a possible mechanism of translational control in rat BACE-1 transcript. We have a paper in press in NAR (submitted September 25th 2003 and accepted March 2nd 2004) dealing with the same issue (De Pietri Tonelli et al., Nucl. Acids Res., 2004, in press). Here we would like to outline substantial differences between our paper and the Rogers et al. one that lead to diverging conclusions.

    Our control experiments clearly reveal that human BACE-1 transcript contains a cryptic promoter that is unraveled by standard DNA transfection. To dissect transcriptional from translational contribution, we adopted an expression system that confines transcription to the sole cytosol. Under these conditions we demonstrate a strong inhibition of translation initiation by BACE-1 transcript leader. This result was fully confirmed by in-vitro translation. Both polysomal analysis and controls on transcript stability are in line with this conclusion. It should also pointed out that in November 2000 we submitted the sequence of a splice variant of the BACE-1 transcript leader (Zacchetti et al., accession number AF324837) detected in human neuroblastoma and exocrine pancreas. Apparently, Rogers and colleagues did not consider the possibility that alternative splicing in the BACE-1 transcript leader might influence their results.

    On the whole, we propose that multiple mechanisms can control the translation in the human BACE-1 transcript, but we also present evidence that shunting does not provide a significant contribution.
    Obviously, we cannot rule out the possibility that the strong discrepancies between the two papers derive from a different control of BACE-1 translation in rat and human, a possibility that, in any extent, would raise a word of caution on the overall discussion of the results.
    Daniele Zacchetti (Zacchetti.Daniele@hsr.it)
    Davide De Pietri Tonelli (depietri@mpi-cbg.de)
    Marija Mihailovich (Mihailovich.Marija@hsr.it)
    Alessandra Di Cesare (DiCesare.Alessandra@hsr.it)
    Franca Codazzi (Codazzi.Franca@hsr.it)
    Fabio Grohovaz (Grohovaz.Fabio@hsr.it)

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