TP53, TP53 Target Genes (DRAM, TIGAR), and Autophagy.

The tumor suppressor gene Tp53 encodes p53, a pivotal transcription factor with a broad target gene repertoire. Induction and stabilization of p53 during DNA damage and oncogene activation function to induce cell cycle arrest, apoptosis, or senescence. These actions are a failsafe to counteract carcinogenesis but Tp53 also plays a key role in regulating different aspects of cell metabolism including autophagy. Autophagy or cellular "self-eating" involves the dismantling and remodeling of cellular components, activities which are fundamental in maintaining cellular homeostasis and in supporting cell growth. After providing an historical overview of Tp53 research, the purpose of this chapter is to review the different mechanistic aspects of Tp53's role in autophagy and to highlight the key challenges which lie ahead. Tp53 functions are regulated by tight control of its cellular levels and notably, Tp53 can be both an activator or inhibitor of autophagy. Under stress conditions such as nutrient depletion or hypoxia, Tp53 contributes to autophagic activation by inhibiting mTOR signaling. Alternatively, p53 can interact with death-associated protein kinase 1 (DAPK1), acting to stabilize nuclear p53 amongst other functions including activation of the key autophagic mediator, Beclin-1. Under normal physiological conditions, Tp53 can inhibit autophagosome formation but stress conditions can also result in Tp53-mediated promotion of autophagy, demonstrating that Tp53 actions are highly context dependent. Tp53 target genes also play key opposing roles in autophagy induction or inhibition such as DRAM and TIGAR, respectively. Finally, the role of Tp53 mutants in autophagy regulation are discussed.