Sp1 and p73 activate PUMA following serum starvation

Ming, Lihua; Sakaida, Tsukasa; Yue, Wen; Jha, Anupma; Zhang, Lin; Yu, Jian

doi:10.1093/carcin/bgn150

Cited by 74 publications

(98 citation statements)

References 48 publications

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“…Expression of Puma for instance can also be induced by FoxO3 and SP1. 26,27 Interestingly, Chirakkal et al 28 identified a SP1-binding site within the bak1 promoter that was also indicated in our MatInspector analysis (Figure 1). This SP1-binding site mediates upregulation of Bak in response to butyrate as well as basal Bak expression.…”

Section: Discussionsupporting

confidence: 72%

Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level

et al. 2011

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During apoptosis Bcl-2 proteins control permeabilization of the mitochondrial outer membrane leading to the release of cytochrome c. Essential gatekeepers for cytochrome c release are the proapoptotic multidomain proteins, Bax, and Bak. The expression of Bax is upregulated upon cellular stress by the tumor suppressor p53. Despite the high functional homology of Bax and Bak, little is known about how the bak gene is regulated. To investigate its transcriptional regulation in further detail, we have analyzed a region spanning 8200 bp upstream of the bak start codon (within exon 2) for transcription factor-binding sites, and identified three p53 consensus sites (BS1-3). Reporter gene assays in combination with site-directed mutagenesis revealed that only one putative p53-binding site (BS3) is necessary and sufficient for induction of reporter gene expression by p53. Consistently, p53 induces expression of endogenous Bak. At the mRNA level, induction of Bak expression is weaker than induction of Puma and p21. Interestingly, Bak expression can also be induced by p73 that binds however to each of the three p53-binding sites within the bak promoter region. Our data suggest that expression of Bak can be induced by both, p53 and p73 utilizing different binding sites within the bak promoter.

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Section: Discussionsupporting

confidence: 72%

Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level

et al. 2011

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“…p73 is a homolog of p53 and has a vital role in mediating apoptosis in a variety of p53 deficient cancer cells (42)(43)(44). In p73-induced apoptosis, p73 triggers the mitochondrial pathway by directly transactivating the Bax and PUMA promoters (42).…”

Section: Discussionmentioning

confidence: 99%

Curcumol triggers apoptosis of p53 mutant triple-negative human breast cancer MDA-MB 231 cells via activation of p73 and PUMA

Huang

Liao

et al. 2017

Oncology Letters

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Abstract. Triple-negative breast cancer (TNBC; estrogen receptor-negative, progesterone receptor-negative and Her-2-negative) is often accompanied by a higher frequency of p53 gene mutations. Therefore, TNBC is challenging to treat due to a lack of biological targets and a poor sensitivity to conventional therapies. Curcumol is a monomer composition isolated from the ethanol extracts of Curcuma wenyujin, a Chinese medicinal herb traditionally used as a cancer remedy. Previous studies have revealed that curcumol is able to block proliferation in various human tumor cell lines. However, the underlying mechanisms have yet to be elucidated. The present study aimed to investigate the anticancer effects of curcumol in the human p53 mutant TNBC MDA-MB-231 cell line and its underlying mechanisms. Cell viability and growth were determined by MTT and a mice xenograft model assay, respectively. Cell cycle distribution was examined by flow cytometry. Apoptosis was evaluated by apoptotic morphology analysis with DAPI staining and flow cytometric analysis following Annexin V/propidium iodide staining. The protein expression in cells was eva luated by immunoblotting. Treatment of MDA-MB-231 cells with curcumol resulted in a significant inhibition of cell proliferation in vitro [half maximal inhibitory concentration (IC 50 )=240.7±85.0 µg/ml for 48 h and IC 50 =100.2±13.5 µg/ml for 72 h]. Curcumol treatment also resulted in the suppression of xenograft growth in vivo (100 or 200 µg/kg for 21 days), as well as G 1 phase arrest and an apoptotic response, which were accompanied by the upregulation of p73 expression and the activation of the expression of p53 upregulated modulator of apoptosis (PUMA) and Bcl-2 antagonistic killer (Bak). No cleavage of poly (ADP-ribose) polymerase was detected. To the best of our knowledge, the present data demonstrate for the first time that curcumol inhibits the growth of MDA-MB-231 cells and triggers p53-independent apoptosis, which may be media ted by the p73-PUMA/Bak signaling pathway. Curcumol may, therefore, be a potential compound for use in the development of novel TNBC therapeutics. IntroductionTriple-negative breast cancer (TNBC; estrogen receptor-negative, progesterone receptor-negative and Her-2-negative) remains challenging to treat due to the innate aggressive biological characteristics and the lack of effective therapies (1,2). TNBCs represent ~15% of all breast cancer cases and are often accompanied by a higher frequency of p53 gene mutations (2,3). The tumor suppressor gene p53 serves a critical role in conferring cancer cell sensitivity to DNA-damaging agents (3). Failure of p53 signaling leads to resistance to chemotherapeutics (3-5). p73 is a member of the p53 gene family. Under certain conditions, p73 is able to replace the p53 function in response to DNA damage, activate the transcription of p53-responsive genes and inhibit cell growth in a p53-like manner by inducing cell cycle arrest and apoptosis (6-8). Therefore, the identification of anticancer drugs able to activate p73 ...

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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%

“…The increase in the PUMA expression level under these conditions is due to the activity of transcription factors such as FoxO3a, Sp1 or p73 [27,38,40]. Cells with deletion of PUMA (PUMA -/ -) were resistant to apoptosis during the deficiency of cytokine/growth factors or following serum starvation [38,40]. The pro-apoptotic activity of PUMA is also involved in the removal of damaged cells under conditions of ischemia/reperfusion.…”

Section: Puma In P53-independent Apoptosismentioning

confidence: 99%

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

Hikisz

Kiliańska

2012

Cellular and Molecular Biology Letters

102

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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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Sp1 and p73 activate PUMA following serum starvation

Cited by 74 publications

References 48 publications

Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level

Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level

Curcumol triggers apoptosis of p53 mutant triple-negative human breast cancer MDA-MB 231 cells via activation of p73 and PUMA

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

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