Gadd45 proteins: relevance to aging, longevity and age-related pathologies

Abstract

The Gadd45 proteins have been intensively studied, in view of their important role in key cellular processes. Indeed, the Gadd45 proteins stand at the crossroad of the cell fates by controlling the balance between cell (DNA) repair, eliminating (apoptosis) or preventing the expansion of potentially dangerous cells (cell cycle arrest, cellular senescence), and maintaining the stem cell pool. However, the biogerontological aspects have not thus far received sufficient attention. Here we analyzed the pathways and modes of action by which Gadd45 members are involved in aging, longevity and age-related diseases. Because of their pleiotropic action, a decreased inducibility of Gadd45 members may have far-reaching consequences including genome instability, accumulation of DNA damage, and disorders in cellular homeostasis - all of which may eventually contribute to the aging process and age-related disorders (promotion of tumorigenesis, immune disorders, insulin resistance and reduced responsiveness to stress). Most recently, the dGadd45 gene has been identified as a longevity regulator in Drosophila. Although further wide-scale research is warranted, it is becoming increasingly clear that Gadd45s are highly relevant to aging, age-related diseases (ARDs) and to the control of life span, suggesting them as potential therapeutic targets in ARDs and pro-longevity interventions.

Fig. 1

The protein–protein interaction network (PPI) of Gadd45α, β and γ with their first-order partners. The PPI data were extracted from the BioGRID database (Stark et al., 2011; http://thebiogrid.org), human interactome release 3.1.71, using the YABNA (Yet Another Biological Networks Analyzer) software program, previously described (Tacutu et al., 2010; http://www.netage-project.org). The graphical output was generated using Cytoscape 2.8.0 (Shannon et al., 2003; http://www.cytoscape.org/). Note that the vast majority of Gadd45 partners form connections with all three Gadd45 proteins. Nodes enclosed in rectangles – unique partners of Gadd45α, β or γ. For the details on gene/protein abbreviations, see Appendix B.

Fig. 2

Map of molecular interactions involving GADD45 proteins and cell signaling pathways generated using Ingenuity Pathway Analysis software (IPA). Top functions identified by IPA were Cell Death, Cell Cycle and Cell Growth and Proliferation. Each of the node shapes denotes the function of the interacting protein or group of proteins. Molecular interactions are indicated by the lines between nodes. For the details on gene/protein abbreviations, see Appendix B.

Fig. 3

Map of molecular interactions of GADD45 proteins related to aging processes. Generated using Ingenuity Pathway Analysis software. Top functions and the node shapes as indicated in Fig. 2. For the details on gene/protein abbreviations, see Appendix B.

Fig. 4

Summary scheme: the main anti-aging and pro-longevity activities of Gadd45 family.