PUMA Induction by FoxO3a Mediates the Anticancer Activities of the Broad-Range Kinase Inhibitor UCN-01

Dudgeon, Crissy; Wang, Peng; Sun, X. F.; Peng, Rui; Sun, Qi; Yu, Jian; Zhang, Lin

doi:10.1158/1535-7163.mct-10-0635

Cited by 59 publications

(75 citation statements)

References 48 publications

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“…Luciferase activities were measured and normalized to those of β-galactosidase, as previously described [30]. Experiments were performed in triplicate and repeated at least three times.…”

Section: Resultsmentioning

confidence: 99%

TAp73 promotes cell survival upon genotoxic stress by inhibiting p53 activity

et al. 2014

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p53 plays a key role in regulating DNA damage response by suppressing cell cycle progression or inducing apoptosis depending on extent of DNA damage. However, it is not clear why mild genotoxic stress favors growth arrest, whereas excessive lesions signal cells to die. Here we showed that TAp73, a p53 homologue thought to have a similar function as p53, restrains the transcriptional activity of p53 and prevents excessive activation of its downstream targets upon low levels of DNA damage, which results in cell cycle arrest. Extensive DNA damage triggers TAp73 depletion through ubiquitin/proteasome-mediated degradation of E2F1, leading to enhanced transcriptional activation by p53 and subsequent induction of apoptosis. These findings provide novel insights into the regulation of p53 function and suggest that TAp73 keeps p53 activity in check in regulating cell fate decisions upon genotoxic stress.

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“…Luciferase activities were measured and normalized to those of β-galactosidase, as previously described [30]. Experiments were performed in triplicate and repeated at least three times.…”

Section: Resultsmentioning

confidence: 99%

TAp73 promotes cell survival upon genotoxic stress by inhibiting p53 activity

et al. 2014

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“…45 Akt directly phosphorylates and inactivates members of the FOXO family, detaining them to cytoplasm. 46 Interestingly, central memory T lymphocytes express high levels of phosphor-FOXO3a, 47 maintaining in this way low levels of proapoptotic and cell cycle arrest FOXO3a target genes like FAS ligand, Bim, and p27, which are downregulated in SS. [48][49][50] Altogether, this evidence strongly suggests that PTEN may enhance the apoptotic resistance of SS cells via FOXO3a, thus contributing with other genetic hits to their malignant expansion.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of PTEN status in Sézary syndrome

Cristofoletti

Picchio

Lazzeri

et al. 2013

Blood

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Key Points• PTEN is downregulated in Sézary syndrome by different mechanisms, mostly by gene deletions and microRNAs.• PTEN deficiency activates AKT in skin resident but not circulating Sezary cells.Sézary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma characterized by recurrent chromosomal alterations, among which, chromosome 10q deletion is very frequent. In this study, we investigated the PTEN status, on locus 10q23, in 44 SS patients; our findings show that PTEN is deleted in 36% of SS cases, whereas PTEN downregulation is observed in almost all of the samples evaluated by quantitative reverse-transcriptase polymerase chain reaction and Western blotting analysis. Neither DNA sequence mutation nor promoter hypermethylation were found at the PTEN locus, but we demonstrate that PTEN level can be also reduced by a group of miRs previously found upregulated and of prognostic relevance in SS; particularly, miR-21, miR-106b, and miR-486 were able to control PTEN abundance either in vitro or in vivo. Finally, because reduced PTEN activates the PI3/AKT-mediated pathway of cell growth and survival, we demonstrate that PTEN deficiency is associated with activated AKT in skin resident but not circulating SS cells, suggesting that the cutaneous milieu may strongly contribute to the SS cell growth. To our knowledge, this is the first study fully exploring the PTEN status in a large cohort of SS patients, unveiling potential elements of clinical utility in this malignancy. (Blood. 2013; 122(20):3511-3520)

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“…One of the best known and most important regulators of PUMA is p53, which is described as tumor suppressor protein [23][24][25][26][27][28]37]. Regulation of PUMA activity may also be determined by the activity of p73 [38,39], Sp1 [38], FoxO3a [40,41], E2F1 [39,42], CHOP [43][44][45][46][47][48], TRB3 [24], AP-1 [48] and c-Myc [49,50].…”

Section: Regulation Of Puma Activitymentioning

confidence: 99%

Puma, a critical mediator of cell death — one decade on from its discovery

Hikisz

Kiliańska

2012

Cellular and Molecular Biology Letters

104

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Abbreviations used: ADI/II -activation domain I/II; Apaf-1 -apoptosis protease activating factor-1; Bad -Bcl-2 associated death promoter; Bak -Bcl-2 antagonist killer; Bax -Bcl-2 associated protein x; Bcl-2 -B-cell leukemia/lymphoma-2; BH1-4 -Bcl-2 homology domains 1-4; Bid -BH3 interacting domain death agonist; Bik -Bcl-2 interacting killer; Bim -Bcl-2 interacting mediator of cell death; Bmf -Bcl-2 modifying factor; Bod -Bcl-2-related ovarian death gene; Bok -Bcl-2 ovarian killer; BS1/2 -p53 binding site 1/2; CHOP -C/EBP homologous protein; DEN -diethylnitrosamine; GSK-3 -glycogen synthase kinase-3; HRK -harakiri, activator of apoptosis ; HSPCs -hematopoietic stem/progenitor cells; HSV-1 -human herpes virus; IKK -IκB kinase; IL-3 -interleukin 3; Lys -lysine; Mcl-1 -myeloid cell leukemia-1; MEFs -mouse embryo fibroblasts; miRNA/miR -microRNA; MLS -mitochondrial localization signal; MOMPmitochondrial outer membrane permeabilization; NOXA (PMAP1) -phorbol-12-myristate-13-acetate-induced protein 1; OMM -outer mitochondrial membrane; PCDprogrammed cell death; PI3K -phosphoinositide 3-kinase; PUMA -p53 upregulated modulator of apoptosis; ROS -reactive oxygen species; Ser -serine; Smac/DIABLOsecond mitochondria-derived activator or caspases/direct IAP binding protein with low pI; TRB3 -tribbles 3 homolog; UV-IR -ultraviolet-gamma irradiation Abstract: PUMA (p53 upregulated modulator of apoptosis) is a pro-apoptotic member of the BH3-only subgroup of the Bcl-2 family. It is a key mediator of p53-dependent and p53-independent apoptosis and was identified 10 years ago. The PUMA gene is mapped to the long arm of chromosome 19, a region that is frequently deleted in a large number of human cancers. PUMA mediates apoptosis thanks to its ability to directly bind known anti-apoptotic members of the Bcl-2 family. It mainly localizes to the mitochondria. The binding of PUMA to the inhibitory members of the Bcl-2 family (Bcl-2-like proteins) via its BH3 domain seems to be a critical regulatory step in the induction of apoptosis. It results in the displacement of the proteins Bax and/or Bak. This is followed by their activation and the formation of pore-like structures on the mitochondrial Unauthenticated Download Date | 5/11/18 3:27 AM CELLULAR & MOLECULAR BIOLOGY LETTERS 647 membrane, which permeabilizes the outer mitochondrial membrane, leading to mitochondrial dysfunction and caspase activation. PUMA is involved in a large number of physiological and pathological processes, including the immune response, cancer, neurodegenerative diseases and bacterial and viral infections.

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PUMA Induction by FoxO3a Mediates the Anticancer Activities of the Broad-Range Kinase Inhibitor UCN-01

Cited by 59 publications

References 48 publications

TAp73 promotes cell survival upon genotoxic stress by inhibiting p53 activity

TAp73 promotes cell survival upon genotoxic stress by inhibiting p53 activity

Comprehensive analysis of PTEN status in Sézary syndrome

Puma, a critical mediator of cell death — one decade on from its discovery

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