Picco Raffaella, Tomasella Andrea, Fogolari Federico, Brancolini Claudio
Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine, Italy.
PLoS One. 2014 Oct 16;9(10):e110610. doi: 10.1371/journal.pone.0110610. eCollection 2014.
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.
控制参与相同生物学过程的基因表达的调控回路常常相互连接。这些回路发挥作用以协调多个基因的表达，并且还能补偿网络中特定元件的功能障碍。半胱天冬酶是在细胞凋亡执行阶段起关键作用的半胱氨酸蛋白酶。在培养的胶质母细胞瘤细胞中沉默半胱天冬酶 -2 的表达会使有限数量的基因上调，其中一些与胆固醇稳态相关。溶酶体酸性脂肪酶 A（LIPA）在两种不同的细胞系中因半胱天冬酶 -2 的下调而上调，并且半胱天冬酶 -2 沉默的细胞在脂滴中显示出胆固醇染色减少。我们通过对 mRNA 表达的大规模分析扩展了这一观察结果。与 166 个参与胆固醇稳态的基因相比，分析了所有半胱天冬酶的共表达情况。在大脑中，层次聚类显示调节性凋亡半胱天冬酶（CASP2、CASP8、CASP9、CASP10）和炎性 CASP1 的表达与几个参与胆固醇稳态的基因相关。这些相关性导致多形性胶质母细胞瘤（GBM）发生改变，特别是对于 CASP1。我们还证明了这些相关性是组织特异性的，在肝脏中降低（CASP9 和 CASP10）或不同（CASP2）。对于一些半胱天冬酶（CASP1、CASP6 和 CASP7），这些相关性可能与脑老化有关。
