MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins

Kobet, Eric; Zeng, Xiaoya; Keller, David M.; Lu, Hua

doi:10.1073/pnas.97.23.12547

Cited by 165 publications

(152 citation statements)

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“…MDM2 inhibits both p53 transcriptional activation and p300-mediated p53 acetylation upon ternary complex formation with p300 and p53 (36 -38). Acetylation of p53 by CBP/p300 mostly occurs in the nucleus (36). Therefore, the increase in cytoplasmic p53-MDM2 complexes in DHCR24-overexpressing cells may account for the observed suppression of p53 acetylation in the nucleus, even after treatment with H 2 O 2 (supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Impairs p53 via Persistent Overexpression of 3β-Hydroxysterol Δ24-Reductase

Nishimura

Kohara

Izumi

et al. 2009

Journal of Biological Chemistry

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Persistent infection with hepatitis C virus (HCV) induces tumorigenicity in hepatocytes.To gain insight into the mechanisms underlying this process, we generated monoclonal antibodies on a genome-wide scale against an HCV-expressing human hepatoblastoma-derived cell line, RzM6-LC, showing augmented tumorigenicity. We identified 3␤-hydroxysterol ⌬24-reductase (DHCR24) from this screen and showed that its expression reflected tumorigenicity. HCV induced the DHCR24 overexpression in human hepatocytes. Ectopic or HCV-induced DHCR24 overexpression resulted in resistance to oxidative stress-induced apoptosis and suppressed p53 activity. DHCR24 overexpression in these cells paralleled the increased interaction between p53 and MDM2 (also known as HDM2), a p53-specific E3 ubiquitin ligase, in the cytoplasm. Persistent DHCR24 overexpression did not alter the phosphorylation status of p53 but resulted in decreased acetylation of p53 at lysine residues 373 and 382 in the nucleus after treatment with hydrogen peroxide. Taken together, these results suggest that DHCR24 is elevated in response to HCV infection and inhibits the p53 stress response by stimulating the accumulation of the MDM2-p53 complex in the cytoplasm and by inhibiting the acetylation of p53 in the nucleus. Hepatitis C virus (HCV)5 is composed of a single-stranded RNA genome of positive polarity (1). Translation of viral proteins is initiated from an internal ribosome entry site (2) and results in a single polypeptide that is subsequently cleaved by host and viral proteases to yield viable proteins (3). The HCV genome does not rely on canonical translation factors and can readily establish chronic infection without integrating into the host genome, resulting in hepatic steatosis and hepatocellular carcinoma (HCC) (4). More than 170 million people worldwide are infected with HCV (5); chronic HCV infection and aging are the major risk factors for HCC (6 -8). Liver cancer is the fifth most common cause of cancer mortality worldwide (9). The frequent inactivation of p53 in human HCC suggests that the loss of p53-dependent apoptosis may promote hepatocarcinogenesis (10). Chronic HCV infection results in chronic liver inflammation and induces endoplasmic reticulum stress and oxidative stress, which are thought to induce hepatocarcinogenesis (11, 12). The mechanistic details underlying HCC development are not fully understood. To gain insight into the molecular mechanisms underlying HCV-induced pathogenesis, we previously established RzM6 cells (13), a human hepatoblastoma (HepG2)-derived cell line in which expression of the full-length HCV genome is controlled by a Cre/loxP system. Expression of the HCV genome promoted anchorage-independent growth of RzM6 cells after 44 days of culture from the onset of HCV expression (RzM6-44d cells) but not in RzM6 cells after 0 days (RzM6-0d cells) (13). In the present study, we generated monoclonal antibodies against RzM6 cells cultured for longer than 44 days (RzM6-LC cells) and then screened the antibodies for their ability to...

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Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Impairs p53 via Persistent Overexpression of 3β-Hydroxysterol Δ24-Reductase

Nishimura

Kohara

Izumi

et al. 2009

Journal of Biological Chemistry

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“…It binds to p53 TAD and inhibits p53-mediated transcription, probably by stereo hindrance so that the transcriptional machinery cannot bind to p53 efficiently. MDM2 can also specifically inhibit acetylation of p53 (39,45,46), which impacts negatively on p53 activities, because acetylation of p53 enhances its binding to the chromatin of its target promoters (42), and may also inhibit ubiquitination of p53, thereby protecting it from degradation (33). Perhaps the most extensively studied aspect of regulation of p53 by MDM2 is its ubiquination of p53 (47).…”

Section: Discussionmentioning

confidence: 99%

Negative Regulation of p53 Functions by Daxx and the Involvement of MDM2

Zhao

Liu

Sidhu

et al. 2004

Journal of Biological Chemistry

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In normal cells p53 activity is tightly controlled and MDM2 is a known negative regulator. Here we show that via its acidic domain, Daxx binds to the COOH-terminal domain of p53, whose positive charges are critical for this interaction, as Lys to Arg mutations preserved, but Lys to Ala or Ser to Glu mutations abolished Daxx-p53 interaction. These results thus implicate acetylation and phosphorylation of p53 in regulating its binding to Daxx. Interestingly, whereas Daxx did not bind to p53 in cells as assessed by immunoprecipitation, MDM2 expression restored p53-Daxx interaction, and this correlated with deacetylation of p53. In p53/MDM2-null mouse embryonic fibroblasts (DKO MEF), Daxx repressed p53 target promoters whose p53-binding elements were required for the repression. Coexpression of Daxx and MDM2 led to further repression. p53 expression in DKO MEF induced apoptosis and Daxx expression relieved this effect. Similarly, in HCT116 cells, Daxx conferred striking resistance to 5-fluorouracil-induced apoptosis. As p53 is required for 5-fluorouracil-induced cell death, our data show that Daxx can suppress cell death induced by p53 overexpression and p53-dependent stress response. Collectively, our data reveal Daxx as a novel negative regulator of p53. Importantly, posttranslational modifications of p53 inhibit Daxx-p53 interaction, thereby relieving negative regulation of p53 by Daxx.The critical role of p53 in tumor suppression is manifested in frequent mutations of the p53 gene in cancers (ϳ50% of all human cancers) and in its inactivation in many other cancers by cellular or viral oncogenes and other epigenetic alterations (1). p53-deficient mice develop normally, although such mice exhibit higher incidence of tumors than their wild-type counterparts, demonstrating a critical role for p53 in suppressing tumors (2). p53 exerts its tumor suppression function by activating expression of genes involved in growth arrest and apoptosis (3, 4), and it can also induce apoptosis directly by binding to Bcl-2 family proteins and triggering cytochrome c release (5). Inducing growth arrest and cell death by p53 can impact negatively on normal cell growth and organismal development. Indeed, deletion of the mdm2 gene, whose product is a negative regulator of p53, results in embryonic lethality, but deletion of both p53 and mdm2 simultaneously completely rescues such lethal phenotype (6, 7). Thus, p53 activity must be tightly controlled under physiological conditions. In addition to MDM2, numerous cellular and viral proteins interact with p53 and these proteins can positively or negatively modulate p53-mediated biological effects. Recently, we and others demonstrated that the transcriptional corepressor Daxx interacts with p53 (8 -10), but the biological significance of this interaction remains to be explored.Daxx was initially identified as a binding protein of Fas death domain and was shown to potentiate Fas-mediated apoptosis (11). Subsequent studies implicate Daxx in promoting apoptosis in diverse stress conditions (12-1...

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“…Phosphorylation of the N terminus of p53 enhances acetylation of the C terminus (Sakaguchi et al, 1998), and these modifications are DNA damage inducible (Sakaguchi et al, 1998;Liu et al, 1999). MDM2 can prevent this acetylation of p53 (Kobet et al, 2000;Ito et al, 2001), and association of p53 with deacetylating complexes provides further levels of control on p53 function (Juan et al, 2000;Luo et al, 2000). Acetylation of p53 is regulated by interaction with the promyelocytic leukaemia protein (PML), a RING domain containing tumour suppressor protein.…”

Section: Regulation Of P53 Activitymentioning

confidence: 99%

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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MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins

Cited by 165 publications

References 50 publications

Hepatitis C Virus Impairs p53 via Persistent Overexpression of 3β-Hydroxysterol Δ24-Reductase

Hepatitis C Virus Impairs p53 via Persistent Overexpression of 3β-Hydroxysterol Δ24-Reductase

Negative Regulation of p53 Functions by Daxx and the Involvement of MDM2

Activation and activities of the p53 tumour suppressor protein

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