Overexpression of Aurora-A in primary cells interferes with S-phase entry by diminishing Cyclin D1 dependent activities

Jantscher, Florian; Pirker, Christine; Mayer, Christoph-Erik; Berger, Walter; Sutterluety, Hedwig

doi:10.1186/1476-4598-10-28

Cited by 16 publications

(13 citation statements)

References 43 publications

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“…7). Although our results contrasted with the view that more AurA accelerates mitotic onset in Xenopus egg extract (43), they agreed with prior studies reporting that AurA overexpression arrests the cell cycle in human cells (27)(28)(29). Adding AurA to cycling extract during late interphase was reported to accelerate mitotic entry (43), but this neither accelerated nor delayed CDK1 activation in our experiments (Fig.…”

Section: Discussionsupporting

confidence: 89%

“…This would consequently allow an increase in P-AurA, delay CDK1 activation, and possibly disrupt other events, including mitotic exit, all of which we observed in our study. This could explain why overexpressing wild-type or inactive AurA produced similar phenotypes in past studies (27,29). This delay did not necessarily result from a nonspecific interaction with increased levels of P-AurA because additional AurA protein was not required to induce this phenotype; treating cycling extract with low concentrations of OA increased AurA(Thr-295) phosphorylation only later during interphase and delayed CDK1 activation.…”

Section: Discussionmentioning

confidence: 64%

“…Not only is the proper timing of AurA activation important to cell cycle progression, but its activity must also be strictly controlled. Overexpression of AurA did not accelerate mitosis, but it arrested proliferation in primary and transformed human cells either before or during cell division (27)(28)(29). These studies underscored that AurA activity must be limited throughout the cell cycle, including during mitosis.…”

mentioning

confidence: 86%

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Evidence toward a Dual Phosphatase Mechanism That Restricts Aurora A (Thr-295) Phosphorylation during the Early Embryonic Cell Cycle

Kang

Srividhya

Ipe

et al. 2014

Journal of Biological Chemistry

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Background: Aurora A is a spindle-regulating mitotic kinase that has been implicated in controlling CDK1 activation. Results: Inducing an abnormal increase in Aurora A(Thr-295) phosphorylation during late interphase delays CDK1 activation. Conclusion: Aurora A (Thr-295) phosphorylation during late interphase competes for phosphatase activity that also promotes CDK1 activation. Significance: Learning how kinases and phosphatases function as a system is essential to understand cell cycle control.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 64%

mentioning

confidence: 86%

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Evidence toward a Dual Phosphatase Mechanism That Restricts Aurora A (Thr-295) Phosphorylation during the Early Embryonic Cell Cycle

Kang

Srividhya

Ipe

et al. 2014

Journal of Biological Chemistry

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“…18,19 Aurora kinases are a family of protein kinases that have a key role in multiple stages of mitosis. 20,21 Overexpression of Aurora kinases, particularly Aurora A, has been demonstrated in a number of solid tumors and hematological malignancies. 22,23 Aurora A has an important role in centrosome maturation, spindle assembly, meiotic maturation and metaphase I spindle orientation.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated Aurora A shRNA driven by stathmin promoter suppressed tumor growth and enhanced paclitaxel chemotherapy sensitivity in human breast carcinoma cells

et al. 2012

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Aurora A has multiple key functions in tumor initiation and progression and is overexpressed in many cancers. Several ongoing clinical trials are assessing the unique therapeutic potential of Aurora-based targeted therapy, but several severe adverse events such as hematopoietic toxicity have been observed in the early-phase clinical trials because Aurora A is also involved in normal cells proliferation process. The strategy to develop tumor-specific inhibition of this target may be an alteration for the treatment of Aurora A overexpression tumors. In this study, we developed a novel tumor-specific RNA interference adenovirus system targeting Aurora A by using stathmin promoter and investigated the effects of it on the proliferation, apoptosis and chemotherapy sensitivity in human breast carcinoma cells both in vitro and in vivo. The results showed that treatment of human breast carcinoma cells (SK-BR-3 and MDA-MB-231) by Aurora A short hairpin RNA (shRNA) driven by stathmin gene promoter not only inhibited the cells proliferation, but also enhanced the chemosensitivity to paclitaxel via downregulation of Aurora A mRNA and protein expression, which further decreased the phosphatidylinositol 3 kinase/Akt and p-BRCA1 protein expression. Furthermore, there were no obvious phenotypes changes observed in normally differentiated epithelial cells of MCF210. Therefore, stathmin promoter-driving Aurora A shRNA adenoviral system may have potential use, with targeted tumor gene silencing effect and as adjuvant tumorspecific therapy method, in the treatment of human breast carcinomas.

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“…Propidium iodide-based DNA content analysis (PI-staining) was performed as described (22). Hypoxic conditions were achieved by incubating the cells in a Heracell 150i incubator (Thermo Scientific, Waltham, MA, USA) at 1% oxygen, 5% CO 2 and 37˚C.…”

Section: Methodsmentioning

confidence: 99%

Expression of microRNA-21 in non-small cell lung cancer tissue increases with disease progression and is likely caused by growth conditional changes during malignant transformation

Haigl

Vanas

Setinek

et al. 2014

International Journal of Oncology

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Abstract. MicroRNAs can govern up to hundred different mRNAs and are important regulators of gene expression programs in development and disease. We analyzed the expression of microRNA-21, one of the most common oncomirs, in non-small cell lung cancer (NSCLC). Using northern blots the microRNA-21 expression levels of NSCLC-derived tissue and cell lines were measured. In line with earlier observations we show that mature microRNA-21 expression levels are highly increased in NSCLC-derived tissue compared to normal lung tissue. Additionally, we demonstrate that microRNA-21 levels correlate with malignancy since its expression in higher staged tumors is significantly more elevated compared to stage 1A. Interestingly, microRNA-21 levels in cultured NSCLC-derived cells are comparable to the expression detected in non-malignant lung tissue. Since microRNA-21 levels showed no fluctuation during the cell cycle, accelerated proliferation of tumor cells is not responsible for microRNA-21 upregulation in the tumor compartment. Similarly to NSCLC-derived cancer cells, the tumor-associated fibroblasts show low expression levels of microRNA-21. Together, these data indicate that rather microenviromental and growth conditional changes than intrinsic features of the cancer cells are responsible for the observed increase of microRNA-21 levels in tumor tissues. Subsequently culturing conditions were changed to assess the impact of co-cultivation with fibroblasts, hypoxia and anchorage-independent growth on microRNA-21 expression. While co-cultivation with tumor-associated fibroblasts had no effect on microRNA-21 expression, both hypoxia and anchorage-independent growth cause a microRNA-21 elevation. In summary, our data demonstrate that growth conditions especially expected in more malignant tumors result in microRNA-21 upregulation explaining the observed increase in higher staged lung cancer tissue, but not in lung cancerderived cells.

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Overexpression of Aurora-A in primary cells interferes with S-phase entry by diminishing Cyclin D1 dependent activities

Cited by 16 publications

References 43 publications

Evidence toward a Dual Phosphatase Mechanism That Restricts Aurora A (Thr-295) Phosphorylation during the Early Embryonic Cell Cycle

Evidence toward a Dual Phosphatase Mechanism That Restricts Aurora A (Thr-295) Phosphorylation during the Early Embryonic Cell Cycle

Adenovirus-mediated Aurora A shRNA driven by stathmin promoter suppressed tumor growth and enhanced paclitaxel chemotherapy sensitivity in human breast carcinoma cells

Expression of microRNA-21 in non-small cell lung cancer tissue increases with disease progression and is likely caused by growth conditional changes during malignant transformation

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