Non-Canonical Cell Death Induced by p53

Abstract

Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms of programmed cell death has gained momentum. p53 is a well characterized tumor suppressor that controls cell proliferation and apoptosis and has also been linked to non-apoptotic, non-canonical cell death mechanisms. p53 impacts these non-canonical forms of cell death through transcriptional regulation of its downstream targets, as well as direct interactions with key players involved in these mechanisms, in a cell type- or tissue context-dependent manner. In this review article, we summarize and discuss the involvement of p53 in several non-canonical modes of cell death, including caspase-independent apoptosis (CIA), ferroptosis, necroptosis, autophagic cell death, mitotic catastrophe, paraptosis, and pyroptosis, as well as its role in efferocytosis which is the process of clearing dead or dying cells.

Keywords: apoptosis; autophagy; caspase-independent apoptosis (CIA); efferocytosis; ferroptosis; mitotic catastrophe; necroptosis; paraptosis; pyroptosis.

Figure 1

Schematic representation of caspase-independent apoptosis (CIA) and its regulation by p53. p53 transcriptionally upregulates AIF, binds and inhibits Bcl-2 and Bcl-xL, and also binds with Bak to induce CIA. AIF: Apoptosis-inducing factor; cyt c: cytochrome c; EndoG: endonuclease G.

Figure 2

Role of p53 in ferroptosis. p53 transcriptionally represses solute carrier family 7 member 11 (SLC7A11), sensitizing cells to ferroptosis. GSH: glutathione; GPX4: glutathione peroxidase 4; ROS: reactive oxygen species; RSL3: Ras selective lethal 3; VDAC: voltage-dependent anion channels.

Figure 3

Mechanisms of necroptosis mediated by p53. p53 induces necroptosis by transactivating necrosis-related factor (NRF) and cathepsin Q and also directly binding with cyclophilin D (cypD). TNF: tumor necrosis factor; MLKL: mixed lineage kinase domain-like protein; miR: microRNA; PTP: permeability transition pore; RIPK: receptor-interacting serine/threonine protein kinase.

Figure 4

Autophagic cell death and its regulation by p53. Nuclear p53 induces autophagic cell death by transcriptionally upregulating tuberous sclerosis (TSC2), AMP-activated protein kinase (AMPK), and damage-regulated autophagy modulator (DRAM), whereas cytoplasmic p53 inhibits autophagic cell death by inducing Beclin-1 degradation. mTOR: mammalian target of rapamycin.

Figure 5

Mitotic catastrophe and its association with p53. p53 inhibits transcription of cyclin-dependent kinase 1 (cdk1) and cyclin B1 to inhibit mitotic catastrophe.

Figure 6

Role of p53 in paraptosis. Δ40p53 (p44) increases insulin-like growth factor I receptor (IGF-IR) levels, which induces paraptosis dependent on mitogen-activated protein kinase (MAPK) member proteins (MEK-2, JNK1).

Figure 7

Caspase-1-mediated pyroptosis. p53 transcriptionally upregulates caspase-1, which could activate pyroptosis. GSDMD: gasdermin D; IL: interleukin.

Figure 8

Non-canonical cell death induced by various stimuli/stress.