Cellular stress responses: cell survival and cell death

Abstract

Cells can respond to stress in various ways ranging from the activation of survival pathways to the initiation of cell death that eventually eliminates damaged cells. Whether cells mount a protective or destructive stress response depends to a large extent on the nature and duration of the stress as well as the cell type. Also, there is often the interplay between these responses that ultimately determines the fate of the stressed cell. The mechanism by which a cell dies (i.e., apoptosis, necrosis, pyroptosis, or autophagic cell death) depends on various exogenous factors as well as the cell's ability to handle the stress to which it is exposed. The implications of cellular stress responses to human physiology and diseases are manifold and will be discussed in this review in the context of some major world health issues such as diabetes, Parkinson's disease, myocardial infarction, and cancer.

Figure 1

Induction of heat shock proteins inhibits apoptosis and promotes cell survival. Exposure of cells to elevated temperatures, oxidative stress, and heavy metals causes accumulation of unfolded proteins, which through activation of HSF1 leads to induction of Hsp27 and Hsp70. These Hsps inhibit apoptosis and promote survival.

Figure 2

ER stress and the unfolded protein response. Stress to the ER stimulates the activation of the three endoplasmic reticulum (ER) stress receptors, PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (Ire1) that are involved in the unfolded protein response (UPR). PERK phosphorylates eukaryotic initiation factor 2 (eIF2α) which inhibits general protein translation, allowing eIF2α-independent translation of ATF4, which activates transcription of chaperones such as GRP78. ATF6 undergoes specific proteolysis in the Golgi apparatus which leads to activation. One of the ATF6 target genes is XBP1. IRE1 catalyzes the alternative splicing of XBP1 mRNA leading to expression of the active XBP1 transcription factor. Together the three arms of the UPR block protein translation, increase chaperone expression and enhance ER-associated protein degradative pathways.

Figure 3

DNA damage responses and cell death. Upon exposure to ionizing radiation or genotoxins, the damage to DNA is a common initial event. DNA double strand breaks (DSBs) or single strand breaks (SSBs) are considered to be key lesions that initiate activation of the DNA damage response. Upon DSBs, ataxia telangiectasia mutated (ATM) is recruited by the MRE-11-Rad50-NBS1 (MRN) complex to sites of broken DNA and phosphorylates downstream substrates such as checkpoint kinase 2 (Chk2), which subsequently phosphorylates p53. Sublethal damage to DNA can engage survival pathways via p21-mediated cell cycle arrest. Alternatively—if the damage is too severe to be repaired—pro-apoptotic p53 target genes are activated including Bax, Puma, Noxa, and Fas, which promote apoptosis. Upon SSBs, it is ataxia telangiectasia and Rad3 related (ATR) that gets activated and phosphorylates Chk1. Chk1 in turn phosphorylates and inhibits cdc25c to mediated G2/M arrest or alternatively cdc25a to promote S-phase arrest.

Figure 4

Oxidative stress and cell death. There is a plethora of stimuli that can trigger the generation of reactive oxygen species (ROS), among them irradiation, toxins, and also normal metabolic processes. A range of different ROS species have been identified, which are kept in check by antioxidant defenses. These include several detoxifying enzymes, for example, catalase, GSH peroxidase, and superoxide dismutase (SOD). If these antioxidants defense mechanisms are too weak, ROS-mediated damage to cellular macromolecules will eventually lead to cell death.