Regulation of apoptosis by PML and the PML-NBs

Bernardi, Rosa; Papa, Antonella; Pandolfi, Pier Paolo

doi:10.1038/onc.2008.305

Cited by 142 publications

(104 citation statements)

References 102 publications

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“…Loss of PML sensitizes mice to physically and chemically induced tumorigenesis. This sensitization correlates with defects of PML Ϫ/Ϫ mouse embryo fibroblasts (MEFs) in apoptotic responses to stimuli such as type I and II interferons, gamma radiation, and ceramide (6,7). Additionally, several mouse models of cancer have shown that loss of PML sensitizes mice to increased tumorigenesis, whereas increased expression of PML has a preventative effect on tumor growth (8 -13).…”

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confidence: 99%

Promyelocytic Leukemia Protein Controls Cell Migration in Response to Hydrogen Peroxide and Insulin-like Growth Factor-1

Reineke

Liu

Kao

2010

Journal of Biological Chemistry

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Promyelocytic leukemia protein (PML) was originally identified as part of a chromosomal translocation that contributes to the development of acute promyelocytic leukemia (APL). Since its discovery, PML has been found to play diverse roles in different cellular processes. Notably, PML has anti-proliferative and pro-apoptotic activity that supports its role as a tumor suppressor. We have previously shown that the peptidyl-prolyl isomerase Pin1 is able to affect cell proliferation and hydrogen perox-

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mentioning

confidence: 99%

Promyelocytic Leukemia Protein Controls Cell Migration in Response to Hydrogen Peroxide and Insulin-like Growth Factor-1

Reineke

Liu

Kao

2010

Journal of Biological Chemistry

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“…It is a key constituent of the punctate nuclear structures known as PML-nuclear bodies (PML-NB) (Ascoli and Maul, 1991;Lamond and Earnshaw, 1998;Ishov et al, 1999;Bernardi et al, 2008). It has been shown that sumoylation is required for PML to form mature nuclear bodies (PML-NBs) (Kamitani et al, 1998;Zhong et al, 2000a;Eskiw et al, 2004;Shen et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation

Wei

et al. 2010

Oncogene

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The PML protein is best known for its role as a tumor suppressor for acute promyelocytic leukemia. Both PML and the key Wnt signaling regulator AXIN regulate p53-dependent apoptosis in response to DNA damage. However, how the two major tumor suppressors coordinate with each other is unknown, and the molecular components orchestrating the PML-induced apoptosis remain enigmatic. Here we show that AXIN interacts with PML in vivo, and further that AXIN, PML and p53 form a ternary complex. Exposure to genotoxic signals including UV and doxorubicin induces AXIN to enter into the nucleus where it colocalizes with PML in the nuclear bodies. Domain-mapping experiments revealed that the C-terminal region (aa 597-832) of AXIN is responsible for its interaction with PML. AXIN fails to activate p53 in PML À/À cells, and conversely, PML is unable to activate p53 in AXIN-null SNU475 cells. Consistently, knockdown with respective siRNAs revealed that AXIN and PML depend on each other to elevate p53-Ser-46 phosphorylation and to induce apoptosis after treatment with genotoxins. Moreover, we found that dominantnegative mutants of PML blocked AXIN-induced p53 activation, and that AXIN promotes PML sumoylation, a modification necessary for PML functions. Our finding has thus provided a new avenue for understanding the mechanism by which PML activates p53 and exerts its role as a tumor suppressor.

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“…12 A possible explanation for why Pml null cells are resistant to many apoptotic stimuli can be ascribed to the fact that PML can act as a pleiotropic factor in the functional regulation of several pro-and antiapoptotic factors. 13 Indeed, PML is functioning as part of a complex tumorsuppressive network. For instance, it is well established that PML is an important factor in the regulation of both p53-dependent and -independent apoptotic pathways.…”

Section: The Promyelocytic Leukemia Proteinmentioning

confidence: 99%

“…For instance, it is well established that PML is an important factor in the regulation of both p53-dependent and -independent apoptotic pathways. 13,14 PML activates p53 by several means: by recruiting p53 to PML-NBs by promoting its acetylation and phosphorylation, [15][16][17][18] and by binding and inhibiting Mdm2, the main negative regulator of p53, [19][20][21] as well as by promoting p53 de-ubiquitination by the ubiquitin protease HAUSP. 22,23 Moreover, PML can act as a suppressor of other major oncogenic pathways, such as the PI3K/Akt pathway, through its ability to interact with the protein phosphatase PP2A and inhibit the nuclear function of Akt, thus leading to suppression of its prosurvival and promitogenic functions.…”

Section: The Promyelocytic Leukemia Proteinmentioning

confidence: 99%

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

2011

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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...

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Regulation of apoptosis by PML and the PML-NBs

Cited by 142 publications

References 102 publications

Promyelocytic Leukemia Protein Controls Cell Migration in Response to Hydrogen Peroxide and Insulin-like Growth Factor-1

Promyelocytic Leukemia Protein Controls Cell Migration in Response to Hydrogen Peroxide and Insulin-like Growth Factor-1

AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation

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

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