Abstract
Regulative circuits controlling expression of genes involved in the same biological processes are frequently interconnected. These circuits operate to coordinate the expression of multiple genes and also to compensate dysfunctions in specific elements of the network. Caspases are cysteine-proteases with key roles in the execution phase of apoptosis. Silencing of caspase-2 expression in cultured glioblastoma cells allows the up-regulation of a limited number of genes, among which some are related to cholesterol homeostasis. Lysosomal Acid Lipase A (LIPA) was up-regulated in two different cell lines in response to caspase-2 down-regulation and cells silenced for caspase-2 exhibit reduced cholesterol staining in the lipid droplets. We expanded this observation by large-scale analysis of mRNA expression. All caspases were analyzed in terms of co-expression in comparison with 166 genes involved in cholesterol homeostasis. In the brain, hierarchical clustering has revealed that the expression of regulative apoptotic caspases (CASP2, CASP8 CASP9, CASP10) and of the inflammatory CASP1 is linked to several genes involved in cholesterol homeostasis. These correlations resulted in altered GBM (Glioblastoma Multiforme), in particular for CASP1. We have also demonstrated that these correlations are tissue specific being reduced (CASP9 and CASP10) or different (CASP2) in the liver. For some caspases (CASP1, CASP6 and CASP7) these correlations could be related to brain aging.
Highlights
Caspases were initially discovered as critical enzymes in the control of apoptosis
An unexpected finding was that the regulative apoptotic caspases (CASP9 and CASP10 in particular) share a correlation pattern with cholesterol genes, to CASP2
The reported strong correlations among these caspases and certain cholesterol genes in a heterogeneous tissue, such as the human brain and in a heterogeneous population, suggest that expression of these genes is influenced by common signaling networks linked to specific biological processes
Summary
Caspases were initially discovered as critical enzymes in the control of apoptosis. Quite soon it was evident that, they can supervise additional biological processes, such as inflammation and differentiation [1,2]. This discovery has granted the dichotomy between apoptotic and non-apoptotic caspases. It has been observed that caspases controlling apoptosis can play specific roles unrelated to cell death [3,4,5]. Caspase-8 can play roles unrelated to apoptosis, such as in NF-kB activation or in limiting necroptosis and caspase-10 has been recently shown to control autophagy [6]
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