Abstract
Caspases play important roles in apoptotic cell death and in some other functions, such as cytokine maturation, inflammation, or differentiation. We show here that the 5′-flanking region of the human CASP-2 gene contains three functional response elements for sterol regulatory element binding proteins (SREBPs), proteins that mediate the transcriptional activation of genes involved in cholesterol, triacylglycerol, and fatty acid synthesis. Exposure of several human cell lines to statins, lipid-lowering drugs that drive SREBP proteolytic activation, induced the CASP-2 gene to an extent similar to that for known targets of SREBP proteins. Adenoviral vector-mediated transfer of active SREBP-2 also induced expression of the CASP-2 gene and the caspase-2 protein and increased the cholesterol and triacylglycerol cellular content. These rises in lipids were strongly impaired following small interfering RNA-mediated silencing of the CASP-2 gene. Taken together, our results identify the human CASP-2 gene as a member of the SREBP-responsive gene battery that senses lipid levels in cells and raise the possibility that caspase-2 participates in the control of cholesterol and triacylglycerol levels.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/.
ACKNOWLEDGMENTS
We thank A. Roth and U. Meyer for the in vivo mice experiment; T. Huby for his gift of the LDLr promoter construct; T. Osborne for his gift of SREBP expression plasmids; A. Bettaieb for his encouragements and suggestions; P. Grimaldi, G. Lizard, and L. Lagrost for their critical reading and suggestions; and F. Ménétrier for his help with lipid staining.
E. Logette was a recipient of a fellowship from the Ministry of Research and Education. S. Solier was appointed by the University Hospital, Dijon. This work was supported by the Ligue Nationale Française contre le Cancer, the Conseil Général de Bourgogne, and the INSERM.