Elevation of cyclin B1, active cdc2, and HuR in cervical neoplasia with human papillomavirus type 18 infection

Cho, Nam Hoon; Kang, Suki; Hong, Seunghun; An, Hee Jung; Choi, Yun Shik; Jeong, Goo Bo; Choi, Heung Kuk

doi:10.1016/j.canlet.2005.02.026

Cited by 27 publications

(20 citation statements)

References 29 publications

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“…A role for the post-transcriptional regulation of RNase-L in its antiviral and tumor suppressive functions predicts that the effectors of this regulation may be inactivated in virus-infected cells and in tumors that have escaped the constraints of RNase-L action. Consistent with this idea, HuR expression was altered in cytomegalovirus-infected cells resulting in a compromised antiviral activity (44), and aberrant regulation of HuR was detected in HPV18-associated cervical neoplasia (45). Altered expression of HuR and HuR target mRNAs has also been reported in cancers of the breast (46), gut (47), ovary (48), and colon (26).…”

Section: ј-Utr-mediated Regulation In the Biologicalmentioning

confidence: 66%

Post-transcriptional Regulation of RNase-L Expression Is Mediated by the 3′-Untranslated Region of Its mRNA

Li¹,

Andersen²,

Ezelle³

et al. 2007

Journal of Biological Chemistry

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RNase-L mediates critical cellular functions including antiviral, pro-apoptotic, and tumor suppressive activities; accordingly, its expression must be tightly regulated. Little is known about the control of RNASEL expression; therefore, we examined the potential regulatory role of a conserved 3-untranslated region (3-UTR) in its mRNA. The 3-UTR mediated a potent decrease in the stability of RNase-L mRNA, and of a chimeric ␤-globin-3-UTR reporter mRNA. AU-rich elements (AREs) are cis-acting regulatory regions that modulate mRNA stability. Eight AREs were identified in the RNase-L 3-UTR, and deletion analysis identified positive and negative regulatory regions associated with distinct AREs. In particular, AREs 7 and 8 served a strong positive regulatory function. HuR is an ARE-binding protein that stabilizes ARE-containing mRNAs, and a predicted HuR binding site was identified in the region comprising AREs 7 and 8. Co-transfection of HuR and RNase-L enhanced RNase-L expression and mRNA stability in a manner that was dependent on this 3-UTR region. Immunoprecipitation demonstrated that RNase-L mRNA associates with a HuR containing complex in intact cells. Activation of endogenous HuR by cell stress, or during myoblast differentiation, increased RNase-L expression, suggesting that RNase-L mRNA is a physiologic target for HuR. HuR-dependent regulation of RNase-L enhanced its antiviral activity demonstrating the functional significance of this regulation. These findings identify a novel mechanism of RNase-L regulation mediated by its 3-UTR.The control of mRNA stability is a potent regulatory mechanism, as small changes in mRNA half-life result in dramatic changes in the mRNA available for translation into functional protein. Such post-transcriptional regulation provides a means to rapidly alter gene expression in response to diverse stimuli, and is frequently observed in genes encoding proteins with essential cellular functions such as proliferation and stress response. One of the most extensively studied RNA decay pathways involves AU-rich elements (AREs) 2 present in the 3Ј-untranslated region (3Ј-UTR) of mRNAs (1). The AUUUA sequence is a loose consensus that is found in many but not all AREs; the absence of a strict sequence motif likely reflects the importance of structural components in ARE function (2). The influence of AREs on mRNA turnover occurs through an interaction with ARE-binding proteins (AREBPs) that can function to destabilize or stabilize target mRNAs by modulating access to the decay machinery. Specifically, AREs modulate deadenylation, and decapping, two critical steps in mRNA decay (3, 4); consistent with a link between mRNA stability and translation, some AREBPs function to regulate translation (5, 6). Several AREBPs have been identified, and genetic manipulation of specific AREBPs in mice, such as HuR and tristetraprolin, resulted in dramatic and complex phenotypes that are associated with inflammation and stress response (7,8). These phenotypes underscore the critical role of AREBPs in gene re...

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Section: ј-Utr-mediated Regulation In the Biologicalmentioning

confidence: 66%

Post-transcriptional Regulation of RNase-L Expression Is Mediated by the 3′-Untranslated Region of Its mRNA

Li¹,

Andersen²,

Ezelle³

et al. 2007

Journal of Biological Chemistry

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“…Deregulated expression of miRNAs in cancer may be associated with gain or loss of chromosomal regions because many miRNA genes are located in fragile sites that are frequently altered in cancer (58,59). In addition, aberrant miRNA expression can occur through epigenetic mechanisms or by defects in miRNA biogenesis (60 -62).…”

Section: Discussionmentioning

confidence: 99%

The RNA-binding Protein HuR Opposes the Repression of ERBB-2 Gene Expression by MicroRNA miR-331-3p in Prostate Cancer Cells

Epis

Barker

Giles

et al. 2011

Journal of Biological Chemistry

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“…Thus, restoration of p53 function by blocking this degradation pathway has been reported as an attractive strategy to ensure an effective intervention (Hietanen et al, 2000;Rampias et al, 2009). Interestingly, beside the abrogation of p53, HPV 18 infection increases Cdk1/cyclin B1-associated activity by stabilizing cyclin B1 mRNA through the upregulation of HuR protein in HPV 18-infected cervical lesions (Cho et al, 2006). Overexpression of cyclin B1 has been reported in invasive cervical cancer and has an important role in cervical carcinogenesis (Zhao et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Restoration of the tumor suppressor p53 by downregulating cyclin B1 in human papillomavirus 16/18-infected cancer cells

et al. 2010

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Abrogation of functional p53 is responsible for malignant cell transformation and the maintenance of malignant state of human papillomavirus-infected cancer cells. Thus, restoration of p53 has been regarded as an important strategy for molecular intervention combating papillomavirus-associated malignancies. We show here that depleting cyclin B1 stabilizes and reactivates p53 in papillomavirusinfected cervical cancer cell lines HeLa and CaSki. HeLa cells depleted of cyclin B1 exhibit mitotic defects in spindle formation and chromosome alignment. Downregulation of cyclin B1 increases p14 alternative reading frame of p16, the positive regulator of p53, and decreases phosphorylation of Ser315 in p53. Whereas RO-3306, a selective inhibitor of cyclin-dependent kinase 1 (Cdk1), suppresses this phosphorylation at Ser315 of p53, ZM447439, targeting Aurora A/B kinases, shows no effect. Further analyses in HeLa cells and HCT116 p53(À/À) cells suggest that the Ser315 phosphorylation by Cdk1 regulates negatively the protein stability and the function of p53. Moreover, increased p53 in HeLa cells is functional by showing its increased downstream effectors p21, mouse double minute 2 and Bax. Restoration of p53 and silencing cyclin B1 render cervical carcinoma cells more susceptible to DNA damage agent camptothecin. Taken together, targeting cyclin B1 might be an attractive strategy for preventing and treating papillomavirus-associated cancer by reactivating p53 and by reducing the Cdk1 activity.

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Elevation of cyclin B1, active cdc2, and HuR in cervical neoplasia with human papillomavirus type 18 infection

Cited by 27 publications

References 29 publications

Post-transcriptional Regulation of RNase-L Expression Is Mediated by the 3′-Untranslated Region of Its mRNA

Post-transcriptional Regulation of RNase-L Expression Is Mediated by the 3′-Untranslated Region of Its mRNA

The RNA-binding Protein HuR Opposes the Repression of ERBB-2 Gene Expression by MicroRNA miR-331-3p in Prostate Cancer Cells

Restoration of the tumor suppressor p53 by downregulating cyclin B1 in human papillomavirus 16/18-infected cancer cells

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