RAC3 more than a nuclear receptor coactivator: a key inhibitor of senescence that is downregulated in aging

Abstract

Receptor-associated coactivator 3 (RAC3) is a nuclear receptor coactivator usually overexpressed in tumors that exerts oncogenic functions in the cytoplasm and the nucleus. Although as part of its oncogenic actions it was previously identified as an inhibitor of apoptosis and autophagy, its expression is required in order to preserve the pluripotency and embryonic stem cell self-renewal. In this work we investigated its role in cellular senescence. We found that RAC3 overexpression in the nontumoral HEK293 cells inhibits the premature senescence induced by hydrogen peroxide or rapamycin. The mechanism involves not only the inhibition of autophagy early induced by these stimuli in the pathway to senescence, but also the increase in levels and nuclear localization of both the cell cycle suppressors p53/p21 and the longevity promoters FOXO1A, FOXO3A and SIRT1. Furthermore, we found that RAC3 overexpression is required in order to maintain the telomerase activity. In tumoral HeLa cells its activity was inhibited by depletion of RAC3 inducing replicative senescence. Moreover, we demonstrated that in vivo, levels of RAC3 are downregulated in the liver from aged as compared with young rats, whereas the levels of p21 are increased, correlating with the expected senescent cell contents in aged tissues. A similar downregulation of RAC3 was observed in the premature and replicative senescence of human fetal WI-38 cells and premature senescence of hepatocyte HepG2 cell line. Taken together, all these results demonstrate that RAC3 is an inhibitor of senescence whose downregulation in aged individuals could be probably a tumor suppressor mechanism, avoiding the clonal expansion of risky old cells having damaged DNA.

Leptin changes differentiation fate and induces senescence in chondrogenic progenitor cells

“…The loss of normal functionality that results from the induction of senescence has been implicated in age-related diseases and tissue degeneration. 31 , 32 , 33 By comparing cartilage tissues that were harvested from the same OA knee joint that displayed different levels of degeneration, we found that the level of leptin was homogeneous and that the impact of leptin was variable. We observed more serious degeneration in cartilage tissues (low Coll-2 expression) with higher Ob-Rb expression (which activates the leptin pathway), higher p53/p21 expression (which induces tissue senescence) and lower Sirt1 expression in the same knee joint ( Figures 6a and b ).…”

Arterial ageing: from endothelial dysfunction to vascular calcification

“…Modifications of microRNAs , signalling or autophagy correlated with ageing determine various structural and physiological changes of the arterial wall that predispose it to atherosclerosis. In particular, inversion of the elastin/collagen ratio and the nonenzymatic glycosylation of some proteins present in the arterial wall, such as collagen, capable of cross‐linking adjacent proteins increase the mechanical vessel rigidity and stiffness.…”

RAC3 influences the chemoresistance of colon cancer cells through autophagy and apoptosis inhibition

“…However, although RAC3 overexpression significantly decreased the IC 50 , the curve of biological response was modified, reaching higher maximal values of cell death. This unexpected result for Oxa concentrations higher than 0.4 μM could be probably explained regarding the anti-senescent and proliferative stimulating role of RAC3 [ 33 ], which perhaps could be increasing the number of cells capable to respond to Oxa stimulation. Therefore, taking together all these results clearly demonstrate that the expression levels of RAC3 may influence the sensitivity to chemotherapeutic drugs, increasing the chemoresistance when is overexpressed.…”