Fei P, Wang W, Kim SH, Wang S, Burns TF, Sax JK et al.. Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. Cancer Cell 6: 597-609

University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Cancer Cell (Impact Factor: 23.52). 01/2005; 6(6):597-609. DOI: 10.1016/j.ccr.2004.10.012
Source: PubMed


p53-dependent apoptosis is a major determinant of its tumor suppressor activity and can be triggered by hypoxia. No p53 target is known to be induced by p53 or to mediate p53-dependent apoptosis during hypoxia. We report that p53 can directly upregulate expression of Bnip3L, a cell death inducer. During hypoxia, Bnip3L is highly induced in wild-type p53-expressing cells, in part due to increased recruitment of p53 and CBP to Bnip3L. Apoptosis is reduced in hypoxia-exposed cells with functional p53 following Bnip3L knockdown. In vivo, Bnip3L knockdown promotes tumorigenicity of wild-type versus mutant p53-expressing tumors. Thus, Bnip3L, capable of attenuating tumorigenicity, mediates p53-dependent apoptosis under hypoxia, which provides a novel understanding of p53 in tumor suppression.

Download full-text


Available from: Eric J Bernhard,
  • Source
    • "They promote mitophagy by interacting with LC3, a protein critical for autophagosome formation [71] [80]. While BNIP3 and NIX are inducible transcriptional targets of HIF-1α, they are also transcriptionally regulated by p53, but in different directions in response to hypoxic conditions in non-neuronal cells such that BNIP3 is downregulated [81] while NIX is upregulated by p53 [82]. Although these regulatory pathways have not yet been established for neurons, both BNIP3 [83] [84] [85] and NIX [86] [87] are upregulated in neurons in response to stress, suggesting that BNIP3 expression may be regulated differently in neurons. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The p53 tumor suppressor plays a central role in dictating cell survival and death as a cellular sensor for a myriad of stresses including DNA damage, oxidative and nutritional stress, ischemia and disruption of nucleolar function. Activation of p53-dependent apoptosis leads to mitochondrial apoptotic changes via the intrinsic and extrinsic pathways triggering cell death execution most notably by release of cytochrome c and activation of the caspase cascade. Although it was previously believed that p53 induces apoptotic mitochondrial changes exclusively through transcription-dependent mechanisms, recent studies suggest that p53 also regulates apoptosis via a transcription-independent action at the mitochondria. Recent evidence further suggests that p53 can regulate necrotic cell death and autophagic activity including mitophagy. An increasing number of cytosolic and mitochondrial proteins involved in mitochondrial metabolism and respiration are regulated by p53, which influences mitochondrial ROS production as well. Cellular redox homeostasis is also directly regulated by p53 through modified expression of pro- and anti-oxidant proteins. Proper regulation of mitochondrial size and shape through fission and fusion assures optimal mitochondrial bioenergetic function while enabling adequate mitochondrial transport to accommodate local energy demands unique to neuronal architecture. Abnormal regulation of mitochondrial dynamics has been increasingly implicated in neurodegeneration, where elevated levels of p53 may have a direct contribution as the expression of some fission/fusion proteins are directly regulated by p53. Thus, p53 may have a much wider influence on mitochondrial integrity and function than one would expect from its well-established ability to transcriptionally induce mitochondrial apoptosis. However, much of the evidence demonstrating that p53 can influence mitochondria through nuclear, cytosolic or intra-mitochondrial sites of action has yet to be confirmed in neurons. Nonetheless, as mitochondria are essential for supporting normal neuronal functions and in initiating/propagating cell death signaling, it appears certain that the mitochondria-related functions of p53 will have broader implications than previously thought in acute and progressive neurological conditions, providing new therapeutic targets for treatment. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction and Neurodegenerative Diseases.
    Biochimica et Biophysica Acta 01/2014; 1842(8). DOI:10.1016/j.bbadis.2013.12.015 · 4.66 Impact Factor
  • Source
    • "Levels of NIX and BNIP3 mRNA were higher in the tumor samples compared to the normal samples in 5/5 and 3/5 cases, respectively [18]. Nix also functions as an effector of Gq-dependent cardiomyopathy, and negatively regulates tumor growth in nude mice injected with U2OS osteosarcoma cells [20]–[22]. Since both high expression of NF-κB and Nix occurred in gliomas, we tried to find the correlation between them in glioma specimens. In this study, the Nix knockdown U251 stable cell line was established and used to detect the expression of NF-κB pathway-related proteins. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous reports indicate that the NIX/BNIP3L gene acts as a pro-apoptotic factor by interacting with BCL2 and BCL-XL, playing an important role in hypoxia-dependent cell death and acting as a tumor suppressor. However, many studies also showed that NIX is linked to a protective role and cell survival in cancer cells. Nuclear factor-κB (NF-κB) can attenuate apoptosis in human cancers in response to chemotherapeutic agents and ionizing radiation. We observed an absence of i-κBα (NF-κB activation inhibitor) expression, but a greater expression of Nix and p-NF-κB proteins in the Nix-wt U251 cells, which was not observed in the Nix-kn cells under hypoxic conditions. Using electrophoretic mobility shift assay (EMSA) and luciferase detection, the activation of NF-κB was detected only in the Nix-wt U251 cells with hypoxia. These data imply that Nix protein might play a role in the positive regulation of the NF-κB pathway. Moreover, 46 cases of glioma also showed high levels of Nix protein expression, which was always accompanied by high p-NF-κB expression. Patients with Nix (+) showed less tissue apoptosis behavior in glioblastoma (GBM), unlike that observed in the Nix-negative patients (-). The same apoptotic tendency was also identified in anaplastic astrocytoma (AA) groups, but not in astrocytoma (AS). On analyzing the Kaplan-Meier curve, better tumor-free survival was observed only in cases of astrocytoma, and not in AA and GBM. Thus, our study indicates that Nix protein might have multiple functions in regulating glioma behaviors. In the low-grade gliomas (astrocytoma) with low expression of NF-κB, the cell death-inducing function that occurs through a Bax mechanism might predominate and act as a tumor suppressor. While in the malignant gliomas (AA and GBM), with higher expression of the NIX gene and with activity of the NF-κB pathway, the oncogene function of Nix was predominant.
    PLoS ONE 09/2012; 7(9):e44559. DOI:10.1371/journal.pone.0044559 · 3.23 Impact Factor
  • Source
    • "This observation that p53 effectively suppressed BNIP3 pro - moter activity under hypoxic conditions is in contrast to its ability to activate the BNIP3L promoter ( Fei et al , 2004 ) . Given the similar role of both BNIP3 and BNIP3L in hypox - ia - induced apoptosis ( Mellor and Harris , 2007 ) , these results suggest that p53 might have a novel function through sup - pressing BNIP3 expression in this pathway . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia stabilizes the tumour suppressor p53, allowing it to function primarily as a transrepressor; however, the function of p53 during hypoxia remains unclear. In this study, we showed that p53 suppressed BNIP3 expression by directly binding to the p53-response element motif and recruiting corepressor mSin3a to the BNIP3 promoter. The DNA-binding site of p53 must remain intact for the protein to suppress the BNIP3 promoter. In addition, taking advantage of zebrafish as an in vivo model, we confirmed that zebrafish nip3a, a homologous gene of mammalian BNIP3, was indeed induced by hypoxia and p53 mutation/knockdown enhanced nip3a expression under hypoxia resulted in cell death enhancement in p53 mutant embryos. Furthermore, p53 protected against hypoxia-induced cell death mediated by p53 suppression of BNIP3 as illustrated by p53 knockdown/loss assays in both human cell lines and zebrafish model, which is in contrast to the traditional pro-apoptotic role of p53. Our results suggest a novel function of p53 in hypoxia-induced cell death, leading to the development of new treatments for ischaemic heart disease and cerebral stroke.
    The EMBO Journal 08/2011; 30(16):3397-415. DOI:10.1038/emboj.2011.248 · 10.43 Impact Factor
Show more