SREBPs (sterol-regulatory-element-binding proteins) are a family of transcription factors that modulate the expression of several enzymes implicated in endogenous cholesterol, fatty acid, triacylglycerol and phospholipid synthesis. In the present study, evidence for SREBP-1 regulation at the translational level is reported. Using several experimental approaches, we have demonstrated that the 5′-UTR (untranslated region) of the SREBP-1a mRNA contains an IRES (internal ribosome entry site). Transfection experiments with the SREBP-1a 5′-UTR inserted in a dicistronic reporter vector showed a remarkable increase in the downstream cistron translation, through a cap-independent mechanism. Insertion of the SREBP-1c 5′-UTR in the same vector also stimulated the translation of the downstream cistron, but the observed effect can be ascribed, at least in part, to a cryptic promoter activity. Cellular stress conditions, such as serum starvation, caused an increase in the level of SREBP-1 precursor and mature form in both Hep G2 and HeLa cells, despite the overall reduction in protein synthesis, whereas mRNA levels for SREBP-1 were unaffected by serum starvation. Transfection experiments carried out with a dicistronic construct demonstrated that the cap-dependent translation was affected more than IRES-mediated translation by serum starvation. The thapsigargin- and tunicamycin-induced UPR (unfolded protein response) also increased SREBP-1 expression in Hep G2 cells, through the cap-independent translation mediated by IRES. Overall, these findings indicate that the presence of IRES in the SREBP-1a 5′-UTR allows translation to be maintained under conditions that are inhibitory to cap-dependent translation.
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Research Article|
July 14 2010
Translational control of the sterol-regulatory transcription factor SREBP-1 mRNA in response to serum starvation or ER stress is mediated by an internal ribosome entry site
Fabrizio Damiano;
Fabrizio Damiano
1Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Science and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy
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Simone Alemanno;
Simone Alemanno
1Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Science and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy
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Gabriele V. Gnoni;
Gabriele V. Gnoni
1
1Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Science and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy
1To whom correspondence should be addressed (email gabriele.gnoni@unisalento.it).
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Luisa Siculella
Luisa Siculella
1Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Science and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy
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Biochem J (2010) 429 (3): 603–612.
Article history
Received:
December 01 2009
Revision Received:
May 26 2010
Accepted:
June 01 2010
Accepted Manuscript online:
June 01 2010
Citation
Fabrizio Damiano, Simone Alemanno, Gabriele V. Gnoni, Luisa Siculella; Translational control of the sterol-regulatory transcription factor SREBP-1 mRNA in response to serum starvation or ER stress is mediated by an internal ribosome entry site. Biochem J 1 August 2010; 429 (3): 603–612. doi: https://doi.org/10.1042/BJ20091827
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