The role of PML in the control of apoptotic cell fate: a new key player at ER–mitochondria sites

Abstract

The development of malignant tumors results from deregulated proliferation or an inability of cells to undergo apoptotic cell death. Experimental works of the past decade have highlighted the importance of calcium (Ca 2 þ ) in the regulation of apoptosis. Several studies indicate that the Ca 2 þ content of the endoplasmic reticulum (ER) determines the cell's sensitivity to apoptotic stress and perturbation of ER Ca 2 þ homeostasis appears to be a key component in the development of several pathological situations. Sensitivity to apoptosis depends on the ability of cells to transfer Ca 2 þ from the ER to the mitochondria. The physical platform for the interplay between the ER and mitochondria is a domain of the ER called the mitochondria-associated membranes (MAMs). The disruption of these contact sites has profound consequences for cellular function, such as imbalances of intracellular Ca 2 þ signaling, cellular stress, and disrupted apoptosis progression. The promyelocytic leukemia (PML) protein has been previously recognized as a critical and essential regulator of multiple apoptotic response. Nevertheless, how PML would exert such broad and fundamental role in apoptosis remained for long time a mystery. In this review, we will discuss how recent results demonstrate that the elusive mechanism whereby the PML tumor suppressor exerts its essential role in apoptosis triggered by Ca 2 þ -dependent stimuli can be attributed to its unexpected and fundamental role at MAMs in the control of the functional cross-talk between ER and mitochondria. The Promyelocytic Leukemia ProteinThe promyelocytic leukemia (PML) protein is a tumor suppressor gene originally identified at the break point of the t(15;17) chromosomal translocation of acute promyelocytic leukemia (APL), a distinct subtype of acute myeloid leukemia. As a consequence of this translocation, PML fuses to the retinoic acid (RA) receptor alpha (RARa) gene. Two fusion genes are generated encoding PML-RARa and RARa-PML fusion proteins, which coexist in the leukemic cells, blocking heamatopoietic differentiation (for a review, see Pandolfi; 1 Salomoni and Pandolfi. 2 PML has, therefore, become the object of intense research on the basis of this premise. Since then, PML has been shown to regulate diverse cellular functions, such as transcriptional regulation, DNA-damage response, sumoylation process, cellular senescence, neoangiogenesis, and, of relevance to this review, apoptosis. 3,4 PML belongs to a large family of proteins harboring a tripartite structure that contains a zinc-finger called the RING motif (R) located N-terminally followed by two additional zincfingers motifs (B-boxes; B) and an a-helical coiled-coil domain (CC), collectively referred to as the RBCC domain. The RBCC domain mediates protein-protein interactions and is responsible for PML multimerization and the formation of macromolecular complexes. The C-terminal region of PML is less structured and varies between PML isoforms. Alternative splicing of C-terminal exons is responsible for the existen...

ER stress–mediated autophagy promotes Myc-dependent transformation and tumor growth

“…Conversely, due to their inability to downregulate protein synthesis, cells with a compromised UPR, such as those with abrogated PERK/eIF2α or IRE1/ XBP1 signaling, are substantially more sensitive to ER-induced cell death than wild-type cells, presumably due to the continuous accumulation of misfolded proteins in the ER, a process termed proteotoxicity (54,56). The mechanisms for ER-induced apoptosis are not completely understood, but there is strong evidence that Ca 2+ release from ER stores induces cytochrome c release from the mitochondria (57,58). This leads to the subsequent activation of caspase-3, -4, and -7 in human cells and of caspase-12 in rodents, which mediate apoptosis (59,60).…”

Recruitment of cyclin G2 to promyelocytic leukemia nuclear bodies promotes dephosphorylation of γH2AX following treatment with ionizing radiation

“…Thus, PML activates FOXO3-dependent transcription of several pro-apoptotic and cell cycle-inhibitory genes. 12,16 PML is phosphorylated by several kinases that are activated by DNA damage or stress, such as ATM, ATR and CHK2. This may regulate PML stability, PML-NB biogenesis and the association of PML with particular proteins.…”

Identification of NCF2/p67phox as a novel p53 target gene

“…ROS are not only generated as a cellular response to exogenous stress stimuli, but also as products of normal aerobic metabolism [53][54][55][56][57][58][59] or as second messengers in various signal transduction pathways.…”