Scarpa E.S.,Laboratory of G Protein mediated Signalling |
Fabrizio G.,Laboratory of G Protein mediated Signalling |
Di Girolamo M.,Laboratory of G Protein mediated Signalling
FEBS Journal | Year: 2013
During the development, progression and dissemination of neoplastic lesions, cancer cells can hijack normal pathways and mechanisms. This includes the control of the function of cellular proteins through reversible post-translational modifications, such as ADP-ribosylation, phosphorylation, and acetylation. In the case of mono-ADP-ribosylation and poly-ADP-ribosylation, the addition of one or several units of ADP-ribose to target proteins occurs via two families of enzymes that can generate ADP-ribosylated proteins: the diphtheria toxin-like ADP-ribosyltransferase (ARTD) family, comprising 17 different proteins that are either poly-ADP-ribosyltransferases or mono-ADP-ribosyltransferases or inactive enzymes; and the clostridial toxin-like ADP-ribosyltransferase family, with four human members, two of which are active mono-ADP-ribosyltransferases, and two of which are enzymatically inactive. In line with a central role for poly-ADP-ribose polymerase 1 in response to DNA damage, specific inhibitors of this enzyme have been developed as anticancer therapeutics and evaluated in several clinical trials. Recently, in combination with the discovery of a large number of enzymes that can catalyse mono-ADP-ribosylation, the role of this modification has been linked to human diseases, such as inflammation, diabetes, neurodegeneration, and cancer, thus revealing the need for the development of specific ARTD inhibitors. This will provide a better understanding of the roles of these enzymes in human physiology and pathology, so that they can be targeted in the future to generate new and efficacious drugs. This review summarizes our present knowledge of the ARTD enzymes that are involved in mono-ADP-ribosylation reactions and that have roles in cancer biology. In particular, the well-documented role of macro-containing ARTD8 in lymphoma and the putative role of ARTD15 in cancer are discussed. A number of intracellular ARTD enzymes that are involved in the post-translational modification, mono-ADP-ribosylation, can have roles in cancer biology. The connection between cancer and ARTD8/PARP14 is well established. ARTD8, a Stat6-interacting protein, is associated with aggressiveness of B-cell lymphomas. The endoplasmic reticulum ARTD15/PARP16 can play a role in the nucleo-cytoplasmic trafficking. A dys-regulation of this process leads to the mislocalisation of oncogenic and tumour-suppressor proteins. © 2013 The Authors Journal compilation © 2013 FEBS.
PubMed | Laboratory of G Protein Mediated Signalling
Type: Journal Article | Journal: Current topics in medicinal chemistry | Year: 2013
The post-translational modifications of proteins by mono- and poly-ADP-ribosylation involve the cleavage of NAD, with the release of its nicotinamide moiety, accompanied by the transfer of a single (mono) or several (poly) ADP-ribose molecules from NAD to a specific amino-acid residue of various cellular proteins. Thus, both mono- and poly-ADP-ribosylation are NAD-consuming reactions. ADP-ribosylation reactions have been reported to have important roles in the nucleus, and in mitochondrial activity. Distinct subcellular NAD pools have been identified, not only in the nucleus and the mitochondria, but also in the endoplasmic reticulum and peroxisomes. Recent reports have shed new light on the correlation between NAD-dependent ADP-ribosylation reactions and the endoplasmic reticulum. We have demonstrated that ARTD15/PARP16 is a novel mono-ADP-ribosyltransferase with a new intracellular location, as it is associated with the endoplasmic reticulum. The endoplasmic reticulum is a membranous network of tubules, vesicles, and cisternae that are interconnected in the cytoplasm of eukaryotic cells. This intracellular compartment is responsible for many cellular functions, including facilitation of protein folding and assembly, biosynthesis of lipids, storage of intracellular Ca, and transport of proteins. ARTD15 might have a role in both the nucleo-cytoplasmic shuttling, through importin1 mono-ADP-ribosylation, and in the unfolded protein response through its ability to ADP-ribosylate two components of this pathway: PERK and IRE1. This review summarizes our present knowledge of the enzymes and targets involved in ADP-ribosylation reactions, with special regard to the novel regulatory reactions that occurs at the level of the endoplasmic reticulum, and that can affect the function of this organelle.
PubMed | Laboratory of G Protein Mediated Signalling
Type: Journal Article | Journal: Current pharmaceutical design | Year: 2013
Post-translational modifications of cellular proteins by mono- or poly-ADP-ribosylation are associated with numerous cellular processes. ADP-ribosylation reactions are important in the nucleus, and in mitochondrial activity, stress response signaling, intracellular trafficking, and cell senescence and apoptosis decisions. These reversible reactions add ADP-ribose to target proteins via specific enzymes to form the ADP-ribosylated protein; the cleaveage of this covalent bond is performed via hydrolases. Deficiencies in these enzymatic activities lead to cell death or tumor formation, thus defining their functional roles and impact on human disease. Unlike mono- ADP-ribosyltransferases, poly-ADP-ribose polymerases (PARPs) have been at the frontline of drug discovery since the 1980s. PARP1 is a valuable therapeutic target, with a central role in responses to DNA damage. With mono-ADP-ribosylation now linked to human diseases, such as inflammation, diabetes, neurodegeneration and cancer metastasis, novel and equally important functions of mono-ADPribosylation in cell signaling pathways can now be defined. Recently, we reported mono-ADP-ribosylation of ADP-ribosylation factor 6 (ARF6), a small G-protein of the Ras superfamily. In addition to its involvement in actin remodeling, plasma membrane reorganization and vesicular transport, ARF6 contributes to cancer progression through activation of cell motility and invasion. Consequently, targeting this modification will counteract the pro-invasive effects of ARF6, providing innovative anti-tumor therapy. This review summarizes our present knowledge of the enzymes and targets involved in ADP-ribosylation reactions, and describes in silico approaches to visualize their site of interaction and to identify the precise site for ADP-ribosylation. This should ultimately improve pharmacological strategies to enhance both anti-tumor efficacy and treatment of a number of inflammatory and neurodegenerative disorders.