FIGURE 15.

Model depicting how PPARβ/δ promotes H-RAS-induced cellular senescence, whereas ER stress attenuates H-RAS-induced cellular senescence. Previous studies showed that PPARβ/δ promotes H-RAS-induced senescence and inhibits cell proliferation by potentiating p-ERK and repressing p-AKT (left and right boxes, respectively) (11). H-RAS-induced senescence is promoted by the RAF/MEK/ERK pathway and inhibited by the PI3K/AKT pathway. This collectively leads to increased expression of proteins that mediate senescence including p16, p21, p27, and p53. PPARβ/δ promotes senescence by inhibiting the PI3K/AKT pathway, allowing for increased RAF/MEK/ERK activity. This was previously shown to be mediated by PPARβ/δ-dependent modulation of RASGRP1, PDPK1, and ILK expression (11). The present studies extend this model (middle box) by showing that ER stress and ER stress-associated UPR attenuates H-RAS-induced cellular senescence by repressing p-ERK and increasing p-AKT signaling. PPARβ/δ represses ER stress by inhibiting p-AKT/mTOR activity leading to promotion of H-RAS-induced cellular senescence and inhibition of cell proliferation.