Chapter 9: Oxidative stress in malignant progression: The role of Clusterin, a sensitive cellular biosensor of free radicals.

Clusterin/Apolipoprotein J (CLU) gene is expressed in most human tissues and encodes for two protein isoforms; a conventional heterodimeric secreted glycoprotein and a truncated nuclear form. CLU has been functionally implicated in several physiological processes as well as in many pathological conditions including ageing, diabetes, atherosclerosis, degenerative diseases, and tumorigenesis. A major link of all these, otherwise unrelated, diseases is that they are characterized by increased oxidative injury due to impaired balance between production and disposal of reactive oxygen or nitrogen species. Besides the aforementioned diseases, CLU gene is differentially regulated by a wide variety of stimuli which may also promote the production of reactive species including cytokines, interleukins, growth factors, heat shock, radiation, oxidants, and chemotherapeutic drugs. Although at low concentration reactive species may contribute to normal cell signaling and homeostasis, at increased amounts they promote genomic instability, chronic inflammation, lipid oxidation, and amorphous aggregation of target proteins predisposing thus cells for carcinogenesis or other age-related disorders. CLU seems to intervene to these processes due to its small heat-shock protein-like chaperone activity being demonstrated by its property to inhibit protein aggregation and precipitation, a main feature of oxidant injury. The combined presence of many potential regulatory elements in the CLU gene promoter, including a Heat-Shock Transcription Factor-1 and an Activator Protein-1 element, indicates that CLU gene is an extremely sensitive cellular biosensor of even minute alterations in the cellular oxidative load. This review focuses on CLU regulation by oxidative injury that is the common molecular link of most, if not all, pathological conditions where CLU has been functionally implicated.