p53 suppresses stress-induced cellular senescence via regulation of autophagy under the deprivation of serum

Abstract. The tumor suppressor p53 is widely known for its ability to induce cell cycle arrest or cell death, there-fore preventing neoplastic progression. Previous studies have demonstrated novel roles for p53 in the regulation of autophagy and senescence. p53 can not only exert cell cycle-arresting and senescence-promoting or suppressing functions, but can also induce autophagic flux, particularly under conditions of nutrient deprivation. The present study demonstrated that p53 was capable of activating autophagy, which permits cell survival under conditions of serum star-vation, and suppresses cellular senescence through inhibition of the mammalian target of rapamycin pathway. These results suggest that active autophagy may be a potential mechanism by which p53 suppresses cellular senescence, in response to serum starvation. The findings of the present study provide a potential mechanism for suppression of senescence by p53. Introduction The tumor suppressor p53, also known as the ‘guardian of the cellular genome’ and the ‘cellular gatekeeper’, is the most commonly mutated gene in human cancer (1,2). p53 genetic or epigenetic inactivation has been reported in ~50% of all human cancers (3). p53 as a tumor suppressor protein, has been shown to orchestrate a transcriptional stress response that may have numerous outcomes, including cell cycle arrest and apoptosis (4). Recent studies have identified novel functions for p53, as a regulator of diverse biological processes, including metabolism, autophagy and senescence (5-8).Autophagy is an evolutionarily conserved catabolic process by which cytoplasmic constituents are sequestered within autophagosomes, and targeted by lysosomes for digestion (9). Various stress signals can induce autophagy, including p53, nutrient deprivation, endoplasmic reticulum stress, hypoxia and other diverse stresses(7,10,11). Autophagy may have either beneficial or detrimental cellular effects, depending on the response to environmental stresses. Increasing evidence suggests that autophagy facilitates cell survival by breaking down cytoplasmic components, in order to provide essential ingredients to maintain cellular metabolism under stressful conditions (12,13). However, in some cases, autophagy may contribute to cell death by extensive digestion of intracellular organelles (14).Cellular senescence is a process leading to irrevers-ible arrest of the cell cycle and increased expression of β-galactosidaseβ- (gal) activity at pH 6. Senescence may be initiated by various insults, including telomere shortening (replicative senescence), oncogene activation, oxidative stress and DNA damage (15). Increasing evidence has shown that cellular senescence has an important role in the control of tumor progression, and by limiting cell proliferation it acts as an anticancer barrier (16,17). It has become increasingly apparent that p53 and the mammalian target of rapamycin (mTOR) pathway are critical mediators of the senescence response. p53 itself functions as either an activator or a repressor of senescence. p53 may induce senescence by activating downstream targets and preventing the block of the mTOR pathway (18). Conversely, in some cases, p53 may negatively regulate senescence by inhibiting the mTOR pathway (19). p53 regulation of senescence is dependent on the inverse correlation between p53 levels and mTOR activation, and both p53 and mTOR are also known for their autophagy-modulatory functions. However, it remains to be determined whether autophagic induction, in response to p53, is associated with the regula-tion of senescence by p53.The present study aimed to investigate the impact of autophagy, induced by p53, on cellular senescence. p53 was