Epigenetic regulation of clusterin/apolipoprotein J expression in retinal pigment epithelial cells

Suuronen, Tiina; Nuutinen, Tapio; Ryhänen, Tuomas; Kaarniranta, Kai; Salminen, Antero

doi:10.1016/j.bbrc.2007.03.135

Cited by 69 publications

(61 citation statements)

References 29 publications

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“…Consistent with the hypothesis that CLU is a negative modulator of tumour growth in mammalians, we found that its expression is down-regulated in PCa (Bettuzzi et al No mutations of CLU have been found yet in human cancer, so it is likely that the mechanism of inactivation is epigenetic. This hypothesis is supported by the frequent observation of CpG island methylation or histone deacetylation in the proximity of the CLU gene in different cancers, including PCa (Lund et al 2006, Hellebrekers et al 2007, Suuronen et al 2007, Rauhala et al 2008.…”

Section: Discussionmentioning

confidence: 78%

The clusterin paradigm in prostate and breast carcinogenesis

Rizzi¹,

Bettuzzi²

2010

Endocrine-Related Cancer

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The biological functions of clusterin (CLU, also known as ApoJ, SGP2, TRPM-2, CLI) have been puzzling the researchers since its first discovery in the early 80's. We know that CLU is a single 9-exons gene expressing three protein forms with different sub-cellular localisations and diverse biological functions. Despite the many reports from many research teams on CLU action and its relation to tumourigenesis, contradictions in the data and alternative hypothesis still exist. Understanding the role of CLU in tumourigenesis is complicated not only by the existence of different protein forms but also by the changes of tumours over time and the selection pressures imposed by treatments such as hormone ablation or chemotherapy. This review focuses on recent discoveries concerning the role of CLU in prostate and breast cancer onset and progression. Although CLU acts primarily as a tumour suppressor in the early stages of carcinogenesis, consistent with its role in the involution of the prostate following castration, late stage cancer may overexpress CLU following chemotherapeutic drugs or hormonal ablation therapy. High expression of secreted or cytoplasmic CLU may represent a pro-survival stimulus because it confers increased resistance to killing by anti-cancer drugs or enhances tumour cell survival in specific niches.

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Section: Discussionmentioning

confidence: 78%

The clusterin paradigm in prostate and breast carcinogenesis

Rizzi¹,

Bettuzzi²

2010

Endocrine-Related Cancer

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“…The APOE-containing deposits also show comparatively low levels of immunoreactivity for two other known drusen constituents, clusterin (17,18,22) and vitronectin (7,27), that have been reported to be biosynthetic products of the RPE. However, following exposure to human serum, immunoreactivity for both clusterin and vitronectin is apparent within these deposits (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Among these are several plasma proteins, the presence of which implies a systemic contribution to their genesis. Although the primary biosynthetic source for most of these circulating molecules is the liver, a number of them are also known to be synthesized locally by RPE cells (15)(16)(17)(18)(19). The respective contributions of RPE-derived and plasma-derived molecules to the process of drusen biogenesis, as well as the relevant molecular interactions leading to drusen deposition, have not yet been fully elucidated.…”

mentioning

confidence: 99%

Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration

Johnson

Forest

Banna

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

180

186

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We introduce a human retinal pigmented epithelial (RPE) cell-culture model that mimics several key aspects of early stage age-related macular degeneration (AMD). These include accumulation of sub-RPE deposits that contain molecular constituents of human drusen, and activation of complement leading to formation of deposit-associated terminal complement complexes. Abundant sub-RPE deposits that are rich in apolipoprotein E (APOE), a prominent drusen constituent, are formed by RPE cells grown on porous supports. Exposure to human serum results in selective, deposit-associated accumulation of additional known drusen components, including vitronectin, clusterin, and serum amyloid P, thus suggesting that specific proteinprotein interactions contribute to the accretion of plasma proteins during drusen formation. Serum exposure also leads to complement activation, as evidenced by the generation of C5b-9 immunoreactive terminal complement complexes in association with APOE-containing deposits. Ultrastructural analyses reveal two morphologically distinct forms of deposits: One consisting of membrane-bounded multivescicular material, and the other of nonmembrane-bounded particle conglomerates. Collectively, these results suggest that drusen formation involves the accumulation of sub-RPE material rich in APOE, a prominent biosynthetic product of the RPE, which interacts with a select group of drusen-associated plasma proteins. Activation of the complement cascade appears to be mediated via the classical pathway by the binding of C1q to ligands in APOE-rich deposits, triggering direct activation of complement by C1q, deposition of terminal complement complexes and inflammatory sequelae. This model system will facilitate the analysis of molecular and cellular aspects of AMD pathogenesis, and the testing of new therapeutic agents for its treatment.A ge-related macular degeneration (AMD) is characterized in its early stages by the presence of extracellular deposits, known as drusen, that accumulate between the basal surface of the retinal pigmented epithelium (RPE) and Bruch's membrane, an extracellular matrix complex that separates the neural retina from the capillary network in the choroid. Early electron microscopic studies suggested that drusen formation may be a consequence of degeneration of the RPE (1-3), initiated by membranous debris shed from its basal surface (4, 5). These early morphological observations have since been confirmed by a number of more recent studies (6-13).Contemporary investigations of the molecular composition of drusen have provided additional insights into their biogenesis. Immunohistochemical and proteomic studies show that drusen contain a variety of protein and lipid components (14, 15). Among these are several plasma proteins, the presence of which implies a systemic contribution to their genesis. Although the primary biosynthetic source for most of these circulating molecules is the liver, a number of them are also known to be synthesized locally by RPE cells (15)(16)(17)(18)(19). The respect...

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“…More specifically, epigenetic factors downregulate CLU gene expression in retinal pigment epithelial cells [29], and hepatitis delta virus epigenetically enhances CLU expression via histone acetylation in human hepatocellular carcinoma cells [30]. Also, oncogenic H-Ras suppresses CLU expression in rat fibroblast cells in a promoter methylation-dependent manner [31], while the CLU gene promoter was found to be methylated in the TRAMP-C2 cell line and in the human prostate cancer cell line LNCaP [32].…”

Section: Apolipoprotein J/clusterin (Clu)mentioning

confidence: 99%

The Molecular Chaperone Apolipoprotein J/Clusterin as a Sensor of Oxidative Stress: Implications in Therapeutic Approaches - A Mini-Review

Trougakos

2013

Gerontology

119

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Background: Organisms are constantly exposed to physiological and environmental stresses and therefore require an efficient surveillance of genome and proteome quality in order to prevent disruption of homeostasis. Central to the intra- and extracellular proteome surveillance system are the molecular chaperones that contribute to both proteome maintenance and clearance. The conventional protein product of the apolipoprotein J/clusterin (CLU) gene is a heterodimeric secreted glycoprotein (also termed as sCLU) with a ubiquitous expression in human tissues. CLU exerts a small heat shock protein-like stress-induced chaperone activity and has been functionally implicated in numerous physiological processes as well as in ageing and most age-related diseases including tumorigenesis, neurodegeneration, and cardiovascular and metabolic syndromes. Objective: The CLU gene is differentially regulated by a wide variety of stimuli due to the combined presence of many distinct regulatory elements in its promoter that make it an extremely sensitive cellular biosensor of environmental and/or oxidative stress. Downstream to CLU gene induction, the CLU protein seems to actively intervene in pathological states of increased oxidative injury due to its chaperone-related property to inhibit protein aggregation and precipitation (a main feature of oxidant injury), as well as due to its reported distribution in both extra- and, most likely, intracellular compartments. Conclusion: On the basis of these findings, CLU has emerged as a unique regulator of cellular proteostasis. Nevertheless, it seemingly exerts a dual function in pathology. For instance, in normal cells and during early phases of carcinogenesis, CLU may inhibit tumor progression as it contributes to suppression of proteotoxic stress. In advanced neoplasia, however, it may offer a significant survival advantage in the tumor by suppressing many therapeutic stressors and enhancing metastasis. This review will critically present a synopsis of recent novel findings that relate to the function of this amazing molecule and support the notion that CLU is a biosensor of oxidative injury; a common link between ageing and all pathologies where CLU has been implicated. Potential future perspectives, implications and opportunities for translational research and the development of new therapies will be discussed.

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Epigenetic regulation of clusterin/apolipoprotein J expression in retinal pigment epithelial cells

Cited by 69 publications

References 29 publications

The clusterin paradigm in prostate and breast carcinogenesis

The clusterin paradigm in prostate and breast carcinogenesis

Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration

The Molecular Chaperone Apolipoprotein J/Clusterin as a Sensor of Oxidative Stress: Implications in Therapeutic Approaches - A Mini-Review

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