EAPP modulates the activity of p21 and Chk2

Andorfer, Peter; Schwarzmayr, Ludwig; Rotheneder, Hans

doi:10.4161/cc.10.13.16247

Cited by 7 publications

(7 citation statements)

References 36 publications

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“…In addition, USF1 levels did not differ between Trp53 KD cells and controls, indicating that USF1 expression is not dependent on p53 ( Figure 2 , A and B). This also suggests that the deficiency in cell cycle arrest of Usf1 KD cells in response to genotoxic stress may be the result of the absence of increased levels and/or activity of p53 and p21 [5] , [6] , [7] , [30] , [31] .…”

Section: Resultsmentioning

confidence: 99%

p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision

et al. 2014

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Genomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway.

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Section: Resultsmentioning

confidence: 99%

p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision

et al. 2014

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“…4B, p21 expression levels were increased when cells contained the BGLF2 expression plasmid relative to the empty plasmid control, confirming that BGLF2 can induce p21 independently from p53. The expression of E2F-associated phosphoprotein (EAPP) is also important for activating p21 transcription and can act independently of p53 (40,41). Therefore, we also examined possible effects of BGLF2 on EAPP levels; however, BGLF2 did not significantly alter EAPP levels relative to those of the empty plasmid control (Fig.…”

Section: Identification Of Herpesvirus Proteins That Induce G 1 /S Acmentioning

confidence: 99%

Identification of Herpesvirus Proteins That Contribute to G ₁ /S Arrest

Paladino

Marcon

Greenblatt

et al. 2014

J Virol

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Lytic infection by herpesviruses induces cell cycle arrest at the G 1 /S transition. This appears to be a function of multiple herpesvirus proteins, but only a minority of herpesvirus proteins have been examined for cell cycle effects. To gain a more comprehensive understanding of the viral proteins that contribute to G 1 /S arrest, we screened a library of over 200 proteins from herpes simplex virus type 1, human cytomegalovirus, and Epstein-Barr virus (EBV) for effects on the G 1 /S interface, using HeLa fluorescent, ubiquitination-based cell cycle indicator (Fucci) cells in which G 1 /S can be detected colorimetrically. Proteins from each virus were identified that induce accumulation of G 1 /S cells, predominantly tegument, early, and capsid proteins. The identification of several capsid proteins in this screen suggests that incoming viral capsids may function to modulate cellular processes. The cell cycle effects of selected EBV proteins were further verified and examined for effects on p53 and p21 as regulators of the G 1 /S transition. Two EBV replication proteins (BORF2 and BMRF1) were found to induce p53 but not p21, while a previously uncharacterized tegument protein (BGLF2) was found to induce p21 protein levels in a p53-independent manner. Proteomic analyses of BGLF2-interacting proteins identified interactions with the NIMA-related protein kinase (NEK9) and GEM-interacting protein (GMIP). Silencing of either NEK9 or GMIP induced p21 without affecting p53 and abrogated the ability of BGLF2 to further induce p21. Collectively, these results suggest multiple viral proteins contribute to G 1 /S arrest, including BGLF2, which induces p21 levels likely by interfering with the functions of NEK9 and GMIP. IMPORTANCEMost people are infected with multiple herpesviruses, whose proteins alter the infected cells in several ways. During lytic infection, the viral proteins block cell proliferation just before the cellular DNA replicates. We used a novel screening method to identify proteins from three different herpesviruses that contribute to this block. Several of the proteins we identified had previously unknown functions or were structural components of the virion. Subsets of these proteins from Epstein-Barr virus were studied for their effects on the cell cycle regulatory proteins p53 and p21, thereby identifying two proteins that induce p53 and one that induces p21 (BGLF2). We identified interactions of BGLF2 with two human proteins, both of which regulate p21, suggesting that BGLF2 induces p21 by interfering with the functions of these two host proteins. Our study indicates that multiple herpesvirus proteins contribute to the cell proliferation block, including components of the incoming virions.

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“…The cyclin-dependent kinase inhibitor p21 is a target of p53 and can be stimulated under oncogenic stress. p21 upregulation was also demonstrated under DNA damage conditions due to an aberrant ratio of Sp1 and E2F transcription factors [11]. Thus, EAPP may be involved in the regulation of self-protective cellular functions in the DNA damage response and anti-apoptotic roles by stimulating p21 protein expression.…”

Section: Introductionmentioning

confidence: 94%

Elevated expression of EAPP is associated with poor prognosis and promotes tumor progression in epithelial ovarian cancer

Shu¹,

Yao²,

Tang³

et al. 2023

ScienceAsia

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E2F-associated phospho-protein (EAPP) is known to be involved in tumor progression. However, its molecular mechanisms in epithelial ovarian cancer (EOC) remain unclear. In the present study, we found that EAPP expression was significantly higher in EOC tissues than in nontumor tissues, and aberrant EAPP expression was significantly correlated with histological grade (p = 0.019), FIGO stage (p = 0.003), histological subtype (p = 0.019), lymph node metastasis (p = 0.024), distant metastasis (p = 0.007), and Ki-67 expression (p < 0.001) in EOC. Patients with high EAPP expression had a significantly lower overall survival rate than those with low EAPP expression. More importantly, univariate and multivariate analyses suggested that the EAPP expression level and distant metastasis are independent prognostic risk factors for EOC patients. Furthermore, we demonstrated that EAPP inhibition using siRNA was associated with decreased cell proliferation and reduced migratory and invasive capability of SK-OV-3 cells, a human EOC cell line. Together, our study reveals that high expression of EAPP may indicate poor prognosis and play an essential role in EOC progression. EAPP may, therefore, serve as a potential biomarker and a novel therapeutic target for EOC patients.

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EAPP modulates the activity of p21 and Chk2

Cited by 7 publications

References 36 publications

p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision

p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision

Identification of Herpesvirus Proteins That Contribute to G ₁ /S Arrest

Elevated expression of EAPP is associated with poor prognosis and promotes tumor progression in epithelial ovarian cancer

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EAPP modulates the activity of p21 and Chk2

Cited by 7 publications

References 36 publications

p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision

p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision

Identification of Herpesvirus Proteins That Contribute to G 1 /S Arrest

Elevated expression of EAPP is associated with poor prognosis and promotes tumor progression in epithelial ovarian cancer

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Identification of Herpesvirus Proteins That Contribute to G ₁ /S Arrest