Clusterin/Apolipoprotein J in human aging and cancer

Abstract

Clusterin/Apolipoprotein J (ApoJ) is a heterodimeric highly conserved secreted glycoprotein being expressed in a wide variety of tissues and found in all human fluids. Despite being cloned since 1989, no genuine function has been attributed to ApoJ so far. The protein has been reportedly implicated in several diverse physiological processes such as sperm maturation, lipid transportation, complement inhibition, tissue remodeling, membrane recycling, cell–cell and cell–substratum interactions, stabilization of stressed proteins in a folding-competent state and promotion or inhibition of apoptosis. ApoJ gene is differentially regulated by cytokines, growth factors and stress-inducing agents, while another defining prominent and intriguing ApoJ feature is its upregulation in many severe physiological disturbances states and in several neurodegenerative conditions mostly related to advanced aging. Moreover, ApoJ accumulates during the viable growth arrested cellular state of senescence, that is thought to contribute to aging and to tumorigenesis suppression; paradoxically ApoJ is also upregulated in several cases of in vivo cancer progression and tumor formation. This review focuses on the reported data related to ApoJ cell-type and signal specific regulation, function and site of action in normal and cancer cells. We discuss the role of ApoJ during cellular senescence and tumorigenesis, especially under the light of the recently demonstrated various ApoJ intracellular protein forms and their interaction with molecules involved in signal transduction and DNA repair, raising the possibility that its overexpression during cellular senescence might cause a predisposition to cancer.

Introduction

Clusterin/Apolipoprotein J (ApoJ) was firstly identified in ram rete testis fluid at 1983 as a secreted glycoprotein enhancing cell aggregation in vitro (named thus as Clusterin) [1] and since then many species homologues were purified and the corresponding genes were cloned. In each case, however, a new name was given for this protein (gene) based on the source of purification (or gene cloning) (Table 1). In humans, it was firstly purified from serum and the cloned gene was named as CLI (complement cytolysis inhibitor) [2], SP-40,40 (secreted protein 40,40) [3] or ApoJ [4] due to similarities with other known apolipoproteins. A comparison of the ApoJ protein sequences among mammalian species reveals a high degree of conservation of ∼70–85%, while attempts to clone its homologues in the worm or the fly by using specific primers spanning the conserved regions of the gene appeared negative (our unpublished results). These two observations along with its wide tissue distribution in animal tissues (see below) and the absence of functional ApoJ polymorphisms in humans ([5], our unpublished data) suggest that the protein has evolved in vertebrates to accomplish a function of fundamental biological importance.

Despite the systematic and combined effort of several groups (a literature survey results in >750 articles) ApoJ function has remained elusive; the main cause being the intriguingly distinct and usually opposing functions proposed in an array of various cell types and tissues, including senescent and cancer cells. ApoJ is upregulated in both senescence (thought to represent a model to study in vivo aging and to protect cells from neoplastic transformation) and in vivo tumorigenesis. In the current report, we review on the ApoJ properties and we attempt to provide an explanation for these seemingly contradictory and confusing expression patterns reported.