Identification of Aurora-A as a Direct Target of E2F3 during G2/M Cell Cycle Progression

He, Lili; Yang, Hua; Ma, Yihong; Pledger, W. J.; Cress, W. Douglas; Cheng, Jin Q.

doi:10.1074/jbc.m803547200

Cited by 38 publications

(38 citation statements)

References 37 publications

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“…E2F3 is a member of cell cycle regulators and can directly bind to the CDE/CHR region of Aurora A promoters and induce Aurora A expression in the G 2 /M phase. 11 The function of E2F3 is regulated by p53 via the p21-CDK-Rb1 pathway. 24 To address whether E2F3 is involved in the upregulation of Aurora A in p53-knockdown cells, we performed a chromatin immunoprecipitation assay, analyzed the sequence of the Aurora A promoter, and found that the Aurora A promoter does contain an E2F binding site ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Such specificity indicates a delicate controlling process. Although the E2F site is known to be present in Aurora A promoter, 11 our studies provide insight into the link between p53 and E2F3 in the regulation of Aurora A transcription and fill an important knowledge gap. It is important to point out that that Aurora A also phosphorylates recombinant Rb1 in vitro (data not shown), which may further enhance the dissociation of E2F3 from Rb1.…”

Section: Disscusionmentioning

confidence: 99%

“…1E) did not lower Aurora A levels, suggesting that only wt p53 is able to downregulate the expression of Aurora A. MED1, have been identified as positive regulators of Aurora A gene expression. [11][12][13] As for posttranscriptional regulation, Fbw7, CHFR, TPX2, phosphatase 2A and AURKAIP1 are involved in regulating the protein stability of Aurora A. [14][15][16][17][18][19][20] However, how the upstream signal/mediators that affect these transcriptional/ posttranscriptional regulators contribute to the expression of Aurora A in cells is largely unclear.…”

Section: P53 Negatively Regulates Aurora a Via Both Transcriptional Amentioning

confidence: 99%

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p53 negatively regulates Aurora A via both transcriptional and posttranslational regulation

Yang

et al. 2012

Cell Cycle

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Section: Resultsmentioning

confidence: 99%

Section: Disscusionmentioning

confidence: 99%

Section: P53 Negatively Regulates Aurora a Via Both Transcriptional Amentioning

confidence: 99%

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p53 negatively regulates Aurora A via both transcriptional and posttranslational regulation

Yang

et al. 2012

Cell Cycle

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“…E2F3, a member of E2F family of transcription factors, binds specifically to RB1 protein, in a cell cycle-dependent manner, and plays a crucial role in the control of genes regulating S phase entry and DNA synthesis. 39,40 Amplification and overexpression of MDM2 on 12q15 were detected in 1 high-grade Ta case that presented with recurrences (Table 2). MDM2 overexpression has been shown to correlate with increasing stages and grades in urinary bladder cancer 41 and MDM2 amplification and TP53 mutation to be mutually exclusive 42 because MDM2 is a specific antagonist of TP53 activity.…”

Section: Discussionmentioning

confidence: 99%

Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma

Nord

Segersten

Sandgren

et al. 2009

Intl Journal of Cancer

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Urinary bladder cancer is a heterogeneous disease with tumors ranging from papillary noninvasive (stage Ta) to solid muscle infiltrating tumors (stage T21). The risk of progression and death for the most frequent diagnosed type, Ta, is low, but the high incidence of recurrences has a significant effect on the patients' quality of life and poses substantial costs for health care systems. Consequently, the purpose of this study was to search for predictive factors of recurrence on the basis of genetic profiling. A clinically well characterized cohort of Ta bladder carcinomas, selected by the presence or absence of recurrences, was evaluated by an integrated analysis of DNA copy number changes and gene expression (clone-based 32K, respectively, U133Plus2.0 arrays). Only a few chromosomal aberrations have previously been defined in superficial bladder cancer. Surprisingly, the profiling of Ta tumors with a high-resolution array showed that DNA copy alterations are relatively common in this tumor type. Furthermore, we observed an overrepresentation of focal amplifications within high-grade and recurrent cases. Known (FGFR3, CCND1, MYC, MDM2) and novel candidate genes were identified within the loci. For example, MYBL2, a nuclear transcription factor involved in cell-cycle progression; YWHAB, an antiapoptotic protein; and SDC4, an important component of focal adhesions represent interesting candidates detected within two amplicons on chromosome 20, for which DNA amplification correlated with transcript up-regulation. The observed overrepresentation of amplicons within high-grade and recurrent cases may be clinically useful for the identification of patients who will benefit from a more aggressive therapy.Urinary bladder cancer is a common malignant disease that ranks fourth among all cancers in Europe with 91,000 new cases and 37,000 deaths annually. 1 The prevalence is 3 to 8 times higher than the incidence, making bladder cancer one of the most prevalent neoplasms, and hence, a major burden for all health care systems. The biology of this disease is heterogeneous with tumors ranging from papillary noninvasive (stage Ta) to solid muscle infiltrating high-grade tumors (stage T2þ). The histologic grade usually parallels the stage, and thus, low-grade is common in lower, whereas high-grade predominates in higher stages. The most frequent form of all newly diagnosed cancers is of the stage Ta category, usually of low grade, which constitute more than half of all newly diagnosed cases. These tumors are considered to evolve from urothelial hyperplasia and are often multifocal. After initial transurethral resection (TUR), approximately 70% recur in the bladder, which makes this tumor type responsible for the high prevalence rate. The risk of progression and death is small, but the frequency of recurrences has a significant effect on the patients' quality of life and poses a substantial cost for the health care systems. Consequently, an attempt to prevent recurrences is frequently made by intravesical instillations either by...

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“…The alternative fates subsequent to postmitotic defects induced by AAK and Aurora B kinase (ABK) inhibition are mediated in part by the p53 and p73 signaling pathways (35,36). In addition, Aurora A inhibition in a range of cell types has been shown to lead to a reduction in the rate of mitotic entry because of a late G 2 block in the cell cycle (37)(38)(39)(40). As is the case for traditional antimitotic agents, this complexity in the downstream cell biological consequences of Aurora A inhibition has led to challenges in the use of the mitotic index as a pharmcodynamic measurement in tumors.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Alisertib (MLN8237), an Investigational Small-Molecule Inhibitor of Aurora A Kinase Using Novel In Vivo Pharmacodynamic Assays

Manfredi

Ecsedy

Chakravarty

et al. 2011

Clinical Cancer Research

264

256

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Purpose: Small-molecule inhibitors of Aurora A (AAK) and B (ABK) kinases, which play important roles in mitosis, are currently being pursued in oncology clinical trials. We developed three novel assays to quantitatively measure biomarkers of AAK inhibition in vivo. Here, we describe preclinical characterization of alisertib (MLN8237), a selective AAK inhibitor, incorporating these novel pharmacodynamic assays.Experimental Design: We investigated the selectivity of alisertib for AAK and ABK and studied the antitumor and antiproliferative activity of alisertib in vitro and in vivo. Novel assays were used to assess chromosome alignment and mitotic spindle bipolarity in human tumor xenografts using immunofluorescent detection of DNA and alpha-tubulin, respectively. In addition, 18F-3 0 -fluoro-3 0 -deoxy-L-thymidine positron emission tomography (FLT-PET) was used to noninvasively measure effects of alisertib on in vivo tumor cell proliferation. Results: Alisertib inhibited AAK over ABK with a selectivity of more than 200-fold in cells and produced a dose-dependent decrease in bipolar and aligned chromosomes in the HCT-116 xenograft model, a phenotype consistent with AAK inhibition. Alisertib inhibited proliferation of human tumor cell lines in vitro and produced tumor growth inhibition in solid tumor xenograft models and regressions in in vivo lymphoma models. In addition, a dose of alisertib that caused tumor stasis, as measured by volume, resulted in a decrease in FLT uptake, suggesting that noninvasive imaging could provide value over traditional measurements of response.Conclusions: Alisertib is a selective and potent inhibitor of AAK. The novel methods of measuring Aurora A pathway inhibition and application of tumor imaging described here may be valuable for clinical evaluation of small-molecule inhibitors. Clin Cancer Res; 17(24); 7614-24. Ó2011 AACR.

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Identification of Aurora-A as a Direct Target of E2F3 during G2/M Cell Cycle Progression

Cited by 38 publications

References 37 publications

p53 negatively regulates Aurora A via both transcriptional and posttranslational regulation

p53 negatively regulates Aurora A via both transcriptional and posttranslational regulation

Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma

Characterization of Alisertib (MLN8237), an Investigational Small-Molecule Inhibitor of Aurora A Kinase Using Novel In Vivo Pharmacodynamic Assays

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