Abstract

Clusterin (CLU) has kept many researchers engaged for a long time since its first discovery and characterization in the attempt to unravel its biological role in mammals. Although there is a general consensus on the fact that CLU is supposed to play important roles in nearly all fundamental biological phenomena and in many human diseases including cancer, after about 10 years of work CLU has been defined as an "enigmatic" protein. This sense of frustration among the researchers is originated by the fact that, despite considerable scientific production concerning CLU, there is still a lack of basic information about the complex regulation of its expression. The CLU gene is a single 9-exon gene expressed at very different levels in almost all major tissues in mammals. The gene produces at least three protein forms with different subcellular localization and diverse biological functions. The molecular mechanism of production of these protein forms remains unclear. The best known is the glycosylated mature form of CLU (sCLU), secreted with very big quantitative differences at different body sites. Hormones and growth factors are the most important regulators of CLU gene expression. Before 2006, it was believed that a unique transcript of about 1.9 kb was originated by transcription of the CLU gene. Now we know that alternative transcriptional initiation, possibly driven by two distinct promoters, may produce at least two distinct CLU mRNA isoforms differing in their unique first exon, named Isoform 1 and Isoform 2. A third transcript, named Isoform 11036, has been recently found as one of the most probable mRNA variants. Approaches like cloning, expression, and functional characterization of the different CLU protein products have generated a critical mass of information teaching us an important lesson about CLU gene expression regulation. Nevertheless, further studies are necessary to better understand the tissue-specific regulation of CLU expression and to identify the specific signals triggering the expression of different/alternative transcript isoforms and protein forms in different cell types at appropriate time.