p53 transcriptional activity is essential for p53-dependent apoptosis following DNA damage

Chao, Connie; Saito, Shinichi; Kang, Jian; Anderson, Carl W.; Appella, Ettore; Xu, Yiming

doi:10.1093/emboj/19.18.4967

Cited by 231 publications

(193 citation statements)

References 56 publications

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“…[1][2][3][4][5] The ability of p53 to act as a transcriptional activator is thought to be important for the induction of apoptosis, since mutant p53 proteins that are defective in transcriptional activation fail to promote apoptosis of cells experiencing DNA damage. 6,7 Numerous transcriptional targets of p53 have been described. Among these are several cell death genes including Bax, Apaf-1, Pidd, and two BH3 (Bcl-2 homology region 3)-only genes, PUMA and Noxa.…”

Section: Introductionmentioning

confidence: 99%

C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage

et al. 2004

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The p53 tumor suppressor promotes apoptosis in response to DNA damage. Here we describe the Caenorhabditis elegans gene ced-13, which encodes a conserved BH3-only protein.We show that ced-13 mRNA accumulates following DNA damage, and that this accumulation is dependent on an intact C. elegans cep-1/p53 gene. We demonstrate that CED-13 protein physically interacts with the antiapoptotic Bcl-2-related protein CED-9. Furthermore, overexpression of ced-13 in somatic cells leads to the death of cells that normally survive, and this death requires the core apoptotic pathway of C. elegans. Recent studies have implicated two BH3-only proteins, Noxa and PUMA, in p53-induced apoptosis in mammals. Our studies suggest that in addition to the BH3-only protein EGL-1, CED-13 might also promote apoptosis in the C. elegans germ line in response to p53 activation. We propose that an evolutionarily conserved pathway exists in which p53 promotes cell death by inducing expression of two BH3-only genes.

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Section: Introductionmentioning

confidence: 99%

C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage

et al. 2004

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“…Cells in which the wild-type p53 was replaced by a transcriptionally inactive mutant showed loss of both cell cycle arrest and apoptotic functions, supporting the importance of transcriptional regulation in these responses (Chao et al, 2000;Jimenez et al, 2000).…”

Section: Apoptosismentioning

confidence: 80%

Activation and activities of the p53 tumour suppressor protein

Bálint¹,

Vousden²

2001

Br J Cancer

275

178

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The p53 tumour suppressor protein inhibits malignant progression by mediating cell cycle arrest, apoptosis or repair following cellular stress. One of the major regulators of p53 function is the MDM2 protein, and multiple forms of cellular stress activate p53 by inhibiting the MDM2-mediated degradation of p53. Mutations in p53, or disruption of the pathways that allow activation of p53, seem to be a general feature of all cancers. Here we review recent advances in our understanding of the pathways that regulate p53 and the pathways that are induced by p53, as well as their implications for cancer therapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

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“…p53 stimulates a wide network of signals to activate the caspases that mediate apoptosis (Strasser et al, 1995). It has been shown that the apoptosis induced by p53 is in large part due to its ability to transcriptionally activate target genes (Chao et al, 2000). Many genes have been identified that are implicated in p53-mediated apoptosis (Vousden and Lu, 2002), such as PUMA and p21.…”

Section: Introductionmentioning

confidence: 99%

PUMA Promotes Bax Translocation by Both Directly Interacting with Bax and by Competitive Binding to Bcl-X_L during UV-induced Apoptosis

Zhang

Xing

Liu

2009

MBoC

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Cell apoptosis induced by UV irradiation is a highly complex process in which different molecular signaling pathways are involved. p53 up-regulated modulator of apoptosis (PUMA) has been proposed as an important regulator in UV irradiation-induced apoptosis. However, the molecular mechanism through which PUMA regulates apoptosis, especially how PUMA activates Bcl-2-associated X protein (Bax) in response to UV irradiation is still controversial. In this study, by using real-time single-cell analysis and fluorescence resonance energy transfer, we investigated the tripartite nexus among PUMA, Bax, and Bcl-X L in living human lung adenocarcinoma cells (ASTC-a-1) to illustrate how PUMA promotes Bax translocation to initiate apoptosis. Our results show that the interaction between PUMA and Bax increased gradually, with Bax translocating to mitochondria and colocalizing with PUMA after UV irradiation, indicating PUMA promotes Bax translocation directly. Simultaneously, the interaction increased markedly between PUMA and Bcl-X L and decreased significantly between Bcl-X L and Bax after UV treatment, suggesting PUMA competitively binds to Bcl-X L to activate Bax indirectly. The above-mentioned results were further confirmed by coimmunoprecipitation experiments. In addition, pifithrin-␣ (a p53 inhibitor) and cycloheximide (a protein synthesis inhibitor) could inhibit PUMA-mediated Bax translocation and cell apoptosis. Together, these studies create an important conclusion that PUMA promotes Bax translocation by both by directly interacting with Bax and by competitive binding to Bcl-X L in UV-induced apoptosis. INTRODUCTIONUV irradiation is a potent carcinogen that can impair cellular functions by directly damaging DNA to induce apoptosis. The cellular response to DNA damage is centered on p53, a transcription factor that exerts its tumor-suppressive function by inducing cell cycle arrest, cell senescence, or apoptosis (Vousden and Lu, 2002). p53 stimulates a wide network of signals to activate the caspases that mediate apoptosis (Strasser et al., 1995). It has been shown that the apoptosis induced by p53 is in large part due to its ability to transcriptionally activate target genes (Chao et al., 2000). Many genes have been identified that are implicated in p53-mediated apoptosis (Vousden and Lu, 2002), such as PUMA and p21. Among the candidate proapoptotic p53 target genes, those that encode mitochondrial proteins such as PUMA stand out because p53-initiated apoptosis seems to proceed through a mitochondrial pathway (Polyak et al., 1997;Li et al., 1999;Soengas et al., 1999;Schuler et al., 2000).p53 up-regulated modulator of apoptosis (PUMA), a member of the Bcl-2 homology (BH)3-only Bcl-2 family proteins, also known as Bcl-2 binding component 3, is a direct transcriptional target of the p53 (Han et al., 2001;Nakano and Vousden, 2001;Yu et al., 2001;Chipuk et al., 2005). PUMA is localized in the mitochondria and induces apoptosis by activating caspases through mitochondrial dysfunction (Nakano and Vousden, 2001;Yu et al., ...

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p53 transcriptional activity is essential for p53-dependent apoptosis following DNA damage

Cited by 231 publications

References 56 publications

C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage

C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage

Activation and activities of the p53 tumour suppressor protein

PUMA Promotes Bax Translocation by Both Directly Interacting with Bax and by Competitive Binding to Bcl-X_L during UV-induced Apoptosis

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p53 transcriptional activity is essential for p53-dependent apoptosis following DNA damage

Cited by 231 publications

References 56 publications

C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage

C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage

Activation and activities of the p53 tumour suppressor protein

PUMA Promotes Bax Translocation by Both Directly Interacting with Bax and by Competitive Binding to Bcl-XL during UV-induced Apoptosis

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PUMA Promotes Bax Translocation by Both Directly Interacting with Bax and by Competitive Binding to Bcl-X_L during UV-induced Apoptosis