PubMed 11715018

HER-2/neu-mediated resistance to DNA-damaging agents requires the activation of Akt, which enhances MDM2-mediated ubiquitination and degradation of p53.

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PubMed 15367689

We investigated the role of the ubiquitin-conjugating enzyme UBCH7 in nuclear receptor transactivation. Using transient transfection assays, we demonstrated that UBCH7 modulates the transcriptional activity of progesterone receptor (PR) and glucocorticoid, androgen, and retinoic acid receptors in a hormone-dependent manner and that the ubiquitin conjugation activity of UBCH7 is required for its ability to potentiate transactivation by steroid hormone receptors (SHR). However, UBCH7 showed no significant effect on the transactivation functions of p53 and VP-16 activation domain. Depletion of endogenous UBCH7 protein by small interfering RNAs suggests that UBCH7 is required for the proper function of SHR. Furthermore, a chromatin immunoprecipitation assay demonstrated the hormone-dependent recruitment of UBCH7 onto estrogen receptor- and PR-responsive promoters. Additionally, we show that UBCH7 and E6-associated protein (E6-AP) synergistically enhance PR transactivation. We also demonstrate that UBCH7 interacts with steroid receptor coactivator 1 (SRC-1) and that UBCH7 coactivation function is dependent on SRC-1. Taken together, our results reveal the possible role of UBCH7 in steroid receptor transactivation and provide insights into the mechanism of action of UBCH7 in receptor function.

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PubMed 17545619

The cytosolic quinone oxidoreductases [NRH:quinone oxidoreductase 2 (NQO2) and NAD(P)H:quinone oxidoreductase 1 (NQO1)] interacted with p53 and protected p53 against 20S proteasomal degradation.

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PubMed 12613199

p19ARF antagonizes the ability of mdm2 to degrade p53, leading to p53 stabilization (p19ARF = CDKN2A)

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PubMed 16931761

The abundance of an essential downstream effecter of this pathway, the tumor suppressor protein p53, is tightly regulated by controlled degradation through COP1 and other E3 ubiquitin ligases, such as MDM2 and Pirh2;

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PubMed 12642697

In concert with these results, Lyn reverses Mdm2-mediated degradation of p53 and increases p53-dependent apoptosis. Our findings support a previously undefined role for nuclear Lyn in both activation and Mdm2-mediated regulation of p53.

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PubMed 10760570

% UbcH7 is a ubiquitin-conjugating enzyme mediating c-fos degradation, transcription factor NF-kappaB maturation, human papilloma virus-mediated p53 and Myc protein degradation, in vitro.

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PubMed 10629057

from full text - MdmX blocks p53 transactivation and degradation ...MdmX is capable of associating with p53

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PubMed 18676821

Mdm2 has long been considered a major p53 regulator that inhibits p53 mainly through ubiquitination followed by proteasomal degradation ( 1

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PubMed 19079265

The turnover rate of p53 is normally high in HeLa cells, but in the presence of miR-29 miRNAs (MIR29A, MIR29B1, MIR29C) p53 became more stable.

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PubMed 14517281

We found that 14-3-3 sigma interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3 sigma expression led to stabilized expression of p53.

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PubMed 15286739

auroraA is known to phosphorylate p53, which leads to its ubiquitylation by MDM2 and subsequent proteolysis

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PubMed 16061648

Furthermore, we found that FIP200 could interact with exogenous and endogenous p53 protein and significantly increase its half-life compared with the control cells ... from full text, U2OS cells

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PubMed 15147952

Using the proteasome-specific inhibitors, MG132 and lactacystin, we show that the p53, the cdk inhibitors p21 and p27, and cyclin A are degraded by the ubiquitin-proteasome pathway in human osteosarcoma cells.

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PubMed 15308643

Both L11 and L23 have been shown to activate p53 by inhibiting MDM2-mediated p53 suppression.

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PubMed 14707282

MDM2 functions as an E3 ubiquitin ligase to degrade p53

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PubMed 15318938

In vitro, nuclear p14arf stabilizes nuclear p53 nuclear p14arf binds Hdm2 to block Hdm2-dependent nucleocytoplasmic shuttling of p53, which is required before cytoplasmic degradation of p53

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PubMed 12972570

Finally, the uba domain is necessary for the ability of full-length hPLIC-2 to interfere with the ubiquitin-mediated proteolysis of p53.

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PubMed 11387205

To investigate possible pathways linking Gas2 to p53, a yeast two-hybrid screen swas performed, indicating m-calpain as a strong Gas2- interacting protein. Moreover, we demonstrate that Gas2 physically interacts with m-calpain in vivo and that recombinant Gas2 inhibits calpain-dependent processing of p53.

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PubMed 17170702

Here, we report that Synoviolin targets tumor suppressor gene p53 for ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm and negatively regulated its cellular level and biological functions, including transcription, cell cycle regulation and apoptosis.

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PubMed 12559172

Akt (PKB) directly phosphorylates multiple protein targets of relevance to apoptosis (Figure 2B), suppressing cell death clearly within the intrinsic pathway (e.g., BAD inactivation, human caspase-9 suppression) and possibly also the extrinsic pathway (e.g., FasL expression) in some types of cells.

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PubMed 14976551

PML-RAR causes deacetylation and degradation of p53, resulting in repression of p53 transcriptional activity

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PubMed 16636671

We report here that enforced Bcl-2 expression in MCF7 cells stabilizes p53, induces phosphorylation of p53 serine 15 (p53pSer15) and inhibits MCF7 cell growth. Bcl-2-positive MCF7 cells proliferate slower than those of Bcl-2 negative.

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PubMed 15527798

MDM2 is an E3 ubiquitin ligase which mediates ubiquitylation and proteasome-dependent degradation of the p53 tumor suppressor protein

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PubMed 9732264

to elucidate the role of nonactive JNK2 in regulating p53 stability the amount of p53-JNK complex was inversely correlated with the p53 level a peptide corresponding to the JNK binding site on p53 efficiently blocked ubiquitination of p53

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PubMed 8576257

The complex of E6-AP and E6 specifically interacts with p53 and mediates ubiquitination of p53 in concert with the E1 ubiquitin-activating enzyme and the E2 ubiquitin-conjugating enzyme UbcH5.

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PubMed 12488444

Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination. Further experiments revealed that overexpression of beta-arrestin 2 enhanced the p53-mediated apoptosis while suppression of endogenous beta-arrestin 2 expression by RNA interference technology considerably attenuated the p53-mediated apoptosis

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PubMed 16849563

Furthermore, hEcd interacts with murine double minute-2 and stabilizes p53 by inhibiting murine double minute-2-mediated degradation of p53

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PubMed 17118707

It has been proposed that ARF is expressed only when an E2F signaling threshold is exceeded following oncogenic activation. The main activity of ARF is its ability to bind to p53 inhibitors and to control ribosome biogenesis. Human double minute (HDM2) [mouse double minute 2 (Mdm2) in mouse] and ARF protein binding 1 (BP1)/Mule are two specific E3 ubiquitin ligases that mediate p53 degradation through ubiquitination.

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PubMed 15592499

Table 1 Substrates of DNA-PK

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PubMed 15480426

Interaction of Jab1 with the tumor suppressor p53 induces CSN-mediated phosphorylation and subsequent degradation of p53 (Bech Otschir et al., 2001).

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PubMed 12584171

ultimate carcinogen benzo[a]pyrene diol epoxide (BPDE) Analyses of proteins in treated cells indicated that p53 was phosphorylated at Ser15 but not at Ser20 within 30 min of treatment, and this correlated with an increase in the total amount of p53 protein.

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PubMed 15295102

Inactivation of endogenous YY1 enhances the accumulation of p53

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PubMed 10892746

In vitro sumoylation of Mdm2 abrogates its self-ubiquitination and increases its ubiquitin ligase activity toward p53

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PubMed 15053879

Substitution of Thr-55 with an alanine residue (T55A) stabilizes p53 and impairs the ability of TAF1 to induce G1 progression.

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PubMed 12485897

the central module is the interplay between p53 and the Mdm2 protein, which inactivates p53 and targets it for rapid proteolysis.

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PubMed 11923280

we find that expression of Akt reduces the protein levels of p53, at least in part by enhancing the degradation of p53.

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PubMed 11431470

In addition, treatment of cells with the PKC activator phorbol ester stimulated the ubiquitination of p53 and reduced its ability to accumulate after stress. H7 did not induce the phosphorylation of human p53 on Ser-15 (Ser-18 in mouse protein), a modification that occurs in response to DNA damage and leads to the release of MDM2 and to transactivation by p53

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PubMed 18340116

Mdm2 binds to p53 and promotes its degradation

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PubMed 12232053

# Ariadne: Our results indicate that NQO1 regulates degradation of p53 in the proteasomes by a mechanism that is independent of both Mdm-2 and ubiquitin. [Regulation] # Ariadne: Inhibition of NQO1 Activity Induces Mdm-2-Independent p53 Degradation That Is Blocked by p14 ARF . [Regulation]

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PubMed 15314174

together to form a ternary complex. We show that, when overexpressed, L23 inhibits HDM2-induced p53 polyubiquitination and degradation and causes a p53-dependent cell cycle arrest.

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PubMed 11431470

We now show that p53 and its inhibitor MDM2 (HDM2 in human cells) are together in the nuclei of H7-treated cells and can be co-immunoprecipitated. Despite this association of p53 with the ubiquitin ligase MDM2, ubiquitinated p53 was not detected in H7-treated cells. Furthermore, co-treatment with H7 and the proteosome inhibitor LLnL prevented the accumulation of ubiquitinated p53 that was observed in cells treated solely with LLnL.

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PubMed 16861890

PCNA and DDB1/CUL4A complexes were found to physically interact with p53 tumor suppressor and its regulator MDM2/HDM2. The isolated CUL4A complexes display potent and robust polyubiquitination activity towards p53 and this activity is dependent on L2DTL, PCNA, DDB1, ROC1 and MDM2/HDM2.

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PubMed 10436023

<p30> p53 is rapidly degraded by the process of ubiquitiation and proteasome. <p31> mdm2 stimulates p53 degradation

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PubMed 16704422

Both VRK2 isoforms have an identical catalytic N-terminal domain and phosphorylate p53 in vitro uniquely in Thr18. Phosphorylation of the p53 protein in response to cellular stresses results in its stabilization by modulating its binding to other proteins.

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PubMed 11331603

despite being expressed at comparable levels (see Fig. 6A), S395D was far less capable of promoting p53 degradation

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PubMed 9724739

In vitro phosphorylation of p53 by JNK abolished Mdm2 binding and targeting of p53 ubiquitination

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PubMed 17297463

p16(INK4a) is a critical component in retinoblastoma protein (Rb)-mediated growth regulatory pathway, p14(ARF) plays a pivotal role in the activation of p53 upon oncogenic stress signals.

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PubMed 15210108

YY1 overexpression stimulates p53 ubiquitination and degradation.

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PubMed 12628923

The COP9 signalosome (CSN) purified from human erythrocytes possesses kinase activity that phosphorylates proteins such as c-Jun and p53 with consequence for their ubiquitin (Ub)-dependent degradation.

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PubMed 12204530

The life history of cancer cells encompasses a series of genetic missteps in which normal cells are progressively transformed into tumor cells that invade surrounding tissues and become malignant. Most prominent among the regulators disrupted in cancer cells are two tumor suppressors, the retinoblastoma protein (RB) and the p53 transcription factor. Here, we discuss interconnecting signaling pathways controlled by RB and p53, attempting to explain their potentially universal involvement in the etiology of cancer. Pinpointing the various ways by which the functions of RB and p53 are subverted in individual tumors should provide a rational basis for developing more refined tumor-specific therapies.

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PubMed 17060456

Western blots revealed that p53 was stabilized in HCT116 PTEN(-/-) cells via an Akt1-dependent and p14(ARF)-independent mechanism

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PubMed 10673501

Upon DNA damage, the amino terminus of p53 is phosphorylated at a number of serine residues including S20, a site that is particularly important in regulating stability and function of the protein.

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PubMed 14559824

Furthermore, by coimmunoprecipitaton and cotransfection assays, we found that PTEN physically binds p53 in vitro as well as in vivo. Binding of PTEN to p53 attenuated MDM2-mediated p53 inhibition.

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PubMed 12297306

p14ARF tumour suppressor stabilises and activates p53 by directly interacting with (H)Mdm2 [(human) murine double minute 2 homologue] and inhibiting its E3 ubiquitin ligase activity. Expression of p14ARF protects p53 from (H)Mdm2-mediated ubiquitylation but has no effect on the auto-ubiquitylation activity of (H)Mdm2 [18].

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PubMed 11358491

Ubiquitination and degradation of p53 is dependent on MDM2...stimulates

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PubMed 18208352

ATM-mediated phosphorylation of p53 stabilizes this tumor suppressor protein by reducing constitutive interactions with MDM2, which usually promotes the degradation of p53 (Figure 1) (Giaccia and Kastan, 1998; Chin et al., 1999).

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Networks
BEL
deg(p(RGD:Tp53)) directlyDecreases p(RGD:Tp53)
Hash
389ae1ce49
Networks

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