Endocrine Abstracts

Cyclic AMP sensitizes human endometrial stromal cells (HESCs) to progesterone and promotes differentiation into decidual cells, a process indispensable for pregnancy. Our studies have shown that cAMP enhances progesterone responses, at least in part, by attenuating ligand-dependent sumoylation of the progesterone receptor (PR). In fact, decidualization is associated with global hyposumoylation and redistribution of SUMO-1 conjugates into distinct nuclear foci. This altered pattern of global sumoylation is not attributable to impaired maturation of SUMO-1 precursor or altered expression of E1 (SAE1/SEA2) or E2 (Ubc9) enzymes but coincides with profound changes in the expression of E3 ligases and SUMO-specific proteases. Specifically, concomitant down-regulation of PIAS1 and up-regulation of the de-conjugating isopeptidase SENP2 limit SUMO-1 modification of ligand-bound PR in decidualizing cells, thereby enhancing the ability of the receptor to activate reporter constructs and endogenous genes. The activity of SUMO conjugating and de-conjugating enzymes is regulated by a variety of environmental stress signals, including free radicals, suggesting that sumoylation serves as a major mechanism for sensing and responding to environmental changes. Interestingly, free radicals such as hydrogen peroxide strongly activate JNK and ERK1/2 signalling, perturbs the cellular sumoylation–desumoylation equilibrium, and impairs progesterone responses in undifferentiated HESCs. In decidual cells, however, selective silencing of JNK activation uncouples the SUMO pathway from oxidative stress signals, thereby ensuring that progesterone responses and cellular homeostasis are maintained.