Copyright © 2007, European Society of Cardiology
PEDF, PPAR-
, p53: Deadly circuits arise when worlds collide
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell' Immacolata, Via Monti di Creta 104, 00167, Roma, Italy
*Corresponding author. Tel.: +39 0666462431; fax: +39 0666462430. gaetano{at}idi.it
Received 6 August 2007; accepted 24 August 2007
See article by Ho et al. [6] (pages 213–223) in this issue.
The superfamily of serine proteinase inhibitors (serpins) is involved in a number of fundamental biological processes such as blood coagulation, complement activation, fibrinolysis, angiogenesis, inflammation and tumor suppression and are expressed in a cell-specific manner [1]. The pigment epithelium-derived factor (PEDF) is a 50-kD serpin that lacks inhibitory properties against either serine or cysteine proteinases [2]. PEDF was first identified in 1987 by Tombran-Tink and Johnson in conditioned medium from foetal human retinal pigment epithelium cell cultures (published in 1991 [3]). PEDF has been shown to be a neurotrophic/differentiation factor and an inhibitor of glial cell proliferation [4]. It is also a protein that is highly up-regulated in the G0 phase of early-passage cells compared with rapidly proliferating cells or senescent cells, and is thus also linked to both the cell cycle and cell senescence. Low-dose PEDF inhibits endothelial cell migration and proliferation, reducing VEGF, FGF-2 and other cytokines-dependent angiogenesis in the rat cornea, and, recently, PEDF has been found to be involved in endothelial cell apoptosis via FAS ligand (FASL) induction and caspase 8 and 9 activation. Although many findings suggest a receptor-like nature of PEDF action, the receptor responsible for its neuroprotective, neurotrophic, and anti-angiogenic effects still remains to be identified. In spite of the elusive nature of its receptor, PEDF triggers a potent intra-cellular cascade of signals leading to NF-
B activation and nuclear translocation [4] as well as phosphorylation of p38 and other MAP kinases [5]. Therefore, the pleiotropic signalling cascades activated by PEDF, suggesting its involvement in events that can lead to both cell survival and death, underscore the potential dual activity of this molecule.
In this issue of Cardiovascular Research novel, functional liaisons between PEDF, PPAR-
and p53 are demonstrated by Ho and colleagues [6] who report that the induction of apoptosis by PEDF in human umbilical endothelial cells is mediated by p53 and involves the induction of PPAR-. The significance of this finding will become apparent after a brief description of the important roles of PPARs and p53 in cellular signalling pathways.
The peroxisome proliferator-activated receptors (PPARs) are ligand-activated intra-cellular transcription factors that have been implicated in important biological processes such as inflammation, tissue remodelling and atherosclerosis [7,8]. PPAR-1 and PPAR-2, the best-studied among PPAR isoforms, modulate proliferation and apoptosis in many cell types. Some long-chain polyunsaturated fatty acids, arachidonic acid metabolites and fatty acid-derived components are natural ligands of PPAR-, while the anti-diabetic thiazolidinedione class of drugs, certain non-steroidal anti-inflammatory drugs and some non-thiazolidinedione tyrosine are the most common synthetic ligands [9]. After activation, PPAR- forms a heterodimer with the retinoid X receptor (RXR) and then binds to specific recognition sites in the target gene, the peroxisome proliferator response elements (PPREs), and regulates transcription [9]. PPAR- has potential anti-neoplastic effects both in solid cancer and in leukaemia through inhibition of cell proliferation, induction of apoptosis and terminal differentiation as well as inhibition of angiogenesis [10]. PPAR- is also expressed in vascular tissues including endothelial cells, smooth muscle cells and macrophages. Increasing evidence suggests that PPAR- is implicated both in the maintenance of vascular homeostasis and in the pathogenesis of a number of vascular conditions such as atherosclerosis, hypertension and restenosis [8].
p53 tumor suppressor protein has long been recognized as the central factor protecting humans from cancer. It has been named "the guardian of the genome" due to its ability to respond to genotoxic stress, such as DNA damage and other stress signals, and to protect the genome by inducing a variety of biological responses including DNA repair, cell cycle arrest, and apoptosis. p53 protein has been shown to limit angiogenesis by at least three mechanisms: 1) interfering with central regulators of hypoxia that mediate angiogenesis, 2) inhibiting production of pro-angiogenic factors, and 3) directly increasing the production of endogenous angiogenesis inhibitors [11]. Interestingly, recent experiments showed that PPAR- binds directly to the nuclear NF-B site located in the promoter region of p53, and chromatin immunoprecipitation experiments demonstrated that PPAR- ligands increase the recruitment of PPAR- on the p53 promoter sequence, increasing its transcription [12]. Further analyses indicated that both PPAR- and p53 are involved in triggering apoptosis by cleavage of caspases-9 and DNA fragmentation [13]. This evidence establishes a functional regulatory link between the world of PPAR hormone-responsive nuclear receptors and p53-dependent signalling.
The study of Ho et al. [6] reports that the apoptotic action of PEDF in human umbilical endothelial cells (HUVECs) involves the induction of PPAR-, which in turn increases p53 expression and activity (Fig. 1). This phenomenon is apparently independent of FASL production and may rely on specific features of HUVECs, suggesting the presence of alternate, endothelial-specific death signalling pathways. This study is the first to describe an involvement of p53 in PEDF-dependent apoptosis, highlighting a novel regulatory mechanism for this multifunctional factor. Several key questions, however, remain to be elucidated: 1) the nature of the PEDF receptor, 2) how PEDF elicits PPAR- transcription, 3) the role of the extra-cellular matrix, and, most importantly, 4) whether different endothelial cells may have different receptors or signalling intermediates activated by PEDF. The potential therapeutic value of PEDF points to the necessity of further investigations to better define its mechanism(s) of action, which will more precisely delineate its range of applications in cancer therapy.
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This work has been partially supported by: grant FIRB # RBLA035A4X-1-FIRB to M.C.C., AIRC regional grant to C.G., UE FP6 grant # UE-LHSB-CT-04-502988 to M.C.C., AFM grant # 12042 to C.G.
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