Illustration of p53 TIAs in lymphocytes. TIAs of p53, via protein-protein interactions with Bcl-2 family members and the mTOR pathway, induce mitochondria-mediated apoptosis and inhibit autophagy. The mechanism for p53-mediated apoptosis is clear, whereas the autophagic role of p53 is not well elucidated. Under stress, PUMA sequestrates Bcl-2 and Bcl-X(L), which associate with cytoplasmic p53. Within 30 minutes, cytoplasmic p53 and proapoptotic proteins translocate to mitochondria. In mitochondria, p53 releases BAX, BAK, BIM, and BID from Bcl-2, Bcl-X(L), BCL2A1, and Mcl-1; BIK, BAD, and Noxa act in similar ways as p53. Their interactions with antiapoptotic Bcl-2, Bcl-X(L) BCL2A1, and Mcl-1 in the cytoplasm are also shown. In addition, transient association of p53 with tBid (BID cleaved by caspase-8 as a result of death-inducing signaling complex activation in extrinsic apoptosis pathway; not shown) or with BAX, BAK, BID, and BAD activates these proapoptotic proteins through structural changes. BAX, BAK, and BID form homo- or hetero-oligomers and trigger mitochondrial outer membrane permeabilization (MOMP) and consequently cytochrome c (cyt c) release. Cyt c then associates with APAF-1, together activating the downstream caspase cascade leading to apoptosis, preceding a second wave of apoptosis triggered by p53 transcription-dependent activities. The effectors in the mitochondrial pathway of apoptosis might vary in different cells by different stimuli. Green arrows indicate positive protein-protein interactions, and red lines, negative protein-protein interactions. Ub indicates ubiquitination; and VDAC1, voltage-dependent anion-selective channel protein 1.