TRIM11 is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth.

TRIM11 (tripartite motif-containing protein 11), an E3 ubiquitin ligase, is known to be involved in the development of the central nervous system. However, very little is known regarding the role of TRIM11 in cancer biology. Here, we examined the expression profile of TRIM11, along with two stem cell markers CD133 and nestin, in multiple glioma patient specimens, glioma primary cultures derived from tumors taken at surgery and normal neural stem/progenitor cells (NSCs). The oncogenic function of TRIM11 in glioma biology was investigated by knockdown and/or overexpression in vitro and in vivo experiments. Our results showed that TRIM11 expression levels were upregulated in malignant glioma specimens and in high-grade glioma-derived primary cultures, whereas remaining low in glioblastoma multiforme (GBM) stable cell lines, low-grade glioma-derived primary cultures and NSCs. The expression pattern of TRIM11 strongly correlated with that of CD133 and nestin and differentiation status of malignant glioma cells. Knock down of TRIM11 inhibited proliferation, migration and invasion of GBM cells, significantly decreased epidermal growth factor receptor (EGFR) levels and mitogen-activated protein kinase activity, and downregulated HB-EGF (heparin-binding EGF-like growth factor) mRNA levels. Meanwhile, TRIM11 overexpression promoted a stem-like phenotype in vitro (tumorsphere formation) and enhanced glial tumor growth in immunocompromised mice. These findings suggest that TRIM11 might be an indicator of glioma malignancy and has an oncogenic function mediated through the EGFR signaling pathway. TRIM11 overexpression potentially leads to a more aggressive glioma phenotype, along with increased malignant tumor growth and poor survival. Taken together, clarification of the biological function of TRIM11 and pathways it affects may provide novel therapeutic strategies for treating malignant glioma patients.

Protein degradation in mitochondria: implications for oxidative stress, aging and disease: a novel etiological classification of mitochondrial proteolytic disorders.

The mitochondrial genome encodes just a small number of subunits of the respiratory chain. All the other mitochondrial proteins are encoded in the nucleus and produced in the cytosol. Various enzymes participate in the activation and intramitochondrial transport of imported proteins. To finally take their place in the various mitochondrial compartments, the targeting signals of imported proteins have to be cleaved by mitochondrial processing peptidases. Mitochondria must also be able to eliminate peptides that are internally synthesized in excess, as well as those that are improperly assembled, and those with abnormal conformation caused by mutation or oxidative damage. Damaged mitochondrial proteins can be removed in two ways: either through lysosomal autophagy, that can account for at most 25-30% of the biochemically estimated rates of average mitochondrial catabolism; or through an intramitochondrial proteinolytic pathway. Mitochondrial proteases have been extensively studied in yeast, but evidence in recent years has demonstrated the existence of similar systems in mammalian cells, and has pointed to the possible importance of mitochondrial proteolytic enzymes in human diseases and ageing. A number of mitochondrial diseases have been identified whose mechanisms involve proteolytic dysfunction. Similar mechanisms probably play a role in diminished resistance to oxidative stress, and in the aging process. In this paper we review current knowledge of mammalian mitochondrial proteolysis, under normal conditions and in several disease states, and we propose an etiological classification of human diseases characterized by a decline or loss of function of mitochondrial proteolytic enzymes.