p53-induced autophagy and senescence

p53, the " cellular gatekeeper " and the " guardian of the cellular genome " , is the most commonly mutated tumor suppressor in human cancer. In response to diverse stresses (that is, DNA damage, nutrient deprivation, oncogenic activation, hypoxia, oxidative stress, hyperproliferative signals and other forms of stress), p53 can be activated and subsequently functions as a transcription factor to orchestrate various biological outputs such as transient cell cycle arrest, apoptosis, cellular senescence, differentiation, metabolism, as well as regulation of autophagy [1]. Autophagy is a dynamic catabolic process by which cytoplasmic components are targeted to a double-membrane vesicle called autophagosomes and subsequently delivered to the lysosome for terminal degradation and recycling [2]. When the cells are subjected to stressful stimuli such as starvation, autophagy is rapidly upregulated to restore their metabolic homeostasis and sustain energy requirements, thus facilitating their survival under stressful conditions. However, excessive or persistent autophagy is also shown to promote cell death. A series of stress signals can induce autophagy, including p53, nutrient deprivation, hypoxia, endoplasmic reticulum stress and so on. The direct evidence from Scherz-Shouval et al. suggests that p53-dependent regulation of autophagy supports cell survival in the face of chronic starvation [3]. The central checkpoints that regulate autophagy are AMP-responsive protein kinase (AMPK) and mammalian target of rapamycin (mTOR) [2]. Cellular senescence is a stress response that accompanies with the irreversible arrest and senescent morphology. Senescence may be initiated by various insults and has an important role in limiting cell proliferation, however, the mechanisms controlling cellular senescence are still debated [4]. Increasing evidence indicate that p53 and AMPK/mTOR pathway are critical mediators of the senescence response [5, 6]. Thus, p53 can induce cell cycle arrest and then active mTOR converts this arrest into senescence (geroconversion). Seemingly paradoxically, p53 can also function as a suppressor of cellular senescence by blocking the mTOR pathway [6]. Both p53 and mTOR are also involved in regulation of autophagy. mTOR inhibits autophagy. However, it remains to be determined whether p53-induced autophagy is associated with suppression of senescence (gerosuppression). We have recently shown that p53 facilitated cell survival by inducing autophagy under the deprivation of serum [7]. Under serum starvation, an increased autophagic flux was observed in the HCT116 p53 +/+ cells but not in the HCT116 p53-/-cells, suggesting that p53 promoted autophagy under serum-starved conditions. we showed p53-dependent autophagy protected cancer cells from starvation-induced death and inhibition of autophagy …