RETRACTED: Regulation of p53: intricate loops and delicate balances

Oren, Moshe; Damalas, Alexander; Gottlieb, Tanya M.; Michael, Dan; Taplick, Jan; Leal, Juan F.M.; Maya, Ruth; Moas, Miri; Seger, Rony; Taya, Yoichi; Ben-Ze’ev, Avri

doi:10.1016/s0006-2952(02)01149-8

Cited by 121 publications

(83 citation statements)

References 30 publications

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“…S1 A). The possibility that CBP depletion might stimulate a p53-stabilizing stress response (22) was investigated by mock or doxorubicin (Dox)-treatment (as positive control for stress stimulus) of control-sh or CBP-shA cells, followed by immunoblotting of lysates for p53 serine 15 (S15) phosphorylation, a marker of p53 activation in response to stress (Fig. S1D) (23,24).…”

Section: Resultsmentioning

confidence: 99%

CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

Shi¹,

Pop²,

Kulikov³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

148

122

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p300 and CREB-binding protein (CBP) act as multifunctional regulators of p53 via acetylase and polyubiquitin ligase (E4) activities. Prior work in vitro has shown that the N-terminal 595 aa of p300 encode both generic ubiquitin ligase (E3) and p53-directed E4 functions. Analysis of p300 or CBP-deficient cells revealed that both coactivators were required for endogenous p53 polyubiquitination and the normally rapid turnover of p53 in unstressed cells. Unexpectedly, p300/CBP ubiquitin ligase activities were absent in nuclear extracts and exclusively cytoplasmic. Consistent with the cytoplasmic localization of its E3/E4 activity, CBP deficiency specifically stabilized cytoplasmic, but not nuclear p53. The N-terminal 616 aa of CBP, which includes the conserved Zn(2+)-binding C/H1-TAZ1 domain, was the minimal domain sufficient to destabilize p53 in vivo, and it included within an intrinsic E3 autoubiquitination activity and, in a two-step E4 assay, exhibited robust E4 activity for p53. Cytoplasmic compartmentalization of p300/CBP\u27s ubiquitination function reconciles seemingly opposed functions and explains how a futile cycle is avoided-cytoplasmic p300/CBP E4 activities ubiquitinate and destabilize p53, while physically separate nuclear p300/CBP activities, such as p53 acetylation, activate p53

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Section: Resultsmentioning

confidence: 99%

CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

Shi¹,

Pop²,

Kulikov³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

148

122

View full text Add to dashboard Cite

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“…Although these functions of p53 are essential to maintain normal cellular homeostasis, if left uncontrolled, they can lead to deleterious consequences. As such, mutations in the p53 gene and aberrations in the p53 signaling pathway pave the way to tumorigenesis (11). Extensive research over the past two decades has placed p53 at the hub of a very complex network of signaling pathways that integrate a variety of intracellular and extracellular inputs.…”

mentioning

confidence: 99%

“…Extensive research over the past two decades has placed p53 at the hub of a very complex network of signaling pathways that integrate a variety of intracellular and extracellular inputs. It is becoming increasingly clear that the opposing effects of various components of the p53 signaling network must be carefully balanced to correctly regulate p53 function and induce the appropriate cellular response (11,12). One such modulator of p53 signaling is ERα.…”

mentioning

confidence: 99%

Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation

Konduri

Medisetty

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

103

115

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Estrogen receptor α (ERα) plays an important role in the onset and progression of breast cancer, whereas p53 functions as a major tumor suppressor. We previously reported that ERα binds to p53, resulting in inhibition of transcriptional regulation by p53. Here, we report on the molecular mechanisms by which ERα suppresses p53's transactivation function. Sequential ChIP assays demonstrated that ERα represses p53-mediated transcriptional activation in human breast cancer cells by recruiting nuclear receptor corepressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). RNAi-mediated down-regulation of NCoR resulted in increased endogenous expression of the cyclin-dependent kinase (CDK)-inhibitor p21 Waf1/Cip1 (CDKN1A) gene, a prototypic transcriptional target of p53. While 17β-estradiol (E2) enhanced ERα binding to p53 and inhibited p21 transcription, antiestrogens decreased ERα recruitment and induced transcription. The effects of estrogen and antiestrogens on p21 transcription were diametrically opposite to their known effects on the conventional ERE-containing ERα target gene, pS2/TFF1. These results suggest that ERα uses dual strategies to promote abnormal cellular proliferation: enhancing the transcription of ERE-containing proproliferative genes and repressing the transcription of p53-responsive antiproliferative genes. Importantly, ERα binds to p53 and inhibits transcriptional activation by p53 in stem/progenitor cell-containing murine mammospheres, suggesting a potential role for the ER-p53 interaction in mammary tissue homeostasis and cancer formation. Furthermore, retrospective studies analyzing response to tamoxifen therapy in a subset of patients with ER-positive breast cancer expressing either wild-type or mutant p53 suggest that the presence of wild-type p53 is an important determinant of positive therapeutic response.nuclear receptor corepressor | mammary epithelial cells | mammospheres | tumor suppressor protein | tamoxifen therapy

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“…p53 WT stabilisation in HMCLs is likely associated with deregulation of p53 expression. This may be because of several mechanisms including alteration of mdm2 activity (Blattner et al, 2002) and/or of ARF expression (Oren et al, 2002). The mechanism by which WT p53 is stabilised in human mesothelioma cells remains to be discovered, but it may be suggested that deregulation of expression is a parameter to consider in the mechanism of mesothelial cell transformation.…”

Section: Discussionmentioning

confidence: 99%

Cell cycle checkpoint status in human malignant mesothelioma cell lines: response to gamma radiation

et al. 2003

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Knowledge of the function of the cell cycle checkpoints in tumour cells may be important to develop treatment strategies for human cancers. The protein p53 is an important factor that regulates cell cycle progression and apoptosis in response to drugs. In human malignant mesothelioma, p53 is generally not mutated, but may be inactivated by SV40 early region T antigen (SV40 Tag). However, the function of p53 has not been investigated in mesothelioma cells. Here, we investigated the function of the cell cycle checkpoints in six human mesothelioma cell lines (HMCLs) by studying the cell distribution in the different phases of the cell cycle by flow cytometry, and expression of cell cycle proteins, p53, p21 WAF1/CIP1 and p27 KIP1 . In addition, we studied p53 gene mutations and expression of SV40 Tag. After exposure to g-radiation, HMCLs were arrested either in one or both phases of the cell cycle, demonstrating a heterogeneity in cell cycle control. G1 arrest was p21 WAF1/CIP1 -and p53-dependent. Lack of arrest in G1 was not related to p53 mutation or binding to SV40 Tag, except in one HMCL presenting a missense mutation at codon 248. These results may help us to understand mesothelioma and develop new treatments.

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RETRACTED: Regulation of p53: intricate loops and delicate balances

Cited by 121 publications

References 30 publications

CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation

Cell cycle checkpoint status in human malignant mesothelioma cell lines: response to gamma radiation

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