Abstract
Aurora-A is a serine/threonine protein kinase and plays an important role in the control of mitotic progression. Dysregulated expression of Aurora-A impairs centrosome separation and maturation, which lead to disrupted cell cycle progression and tumorigenesis. However, the molecular mechanism by which Aurora-A causes cell malignant transformation remains to be further defined. In this report, using transcription factors array and mRNA expression profiling array, we found that overexpression of Aurora-A suppressed transcription activity of AP-2α, a tumor suppressor that is often downregulated in variety of tumors, and inhibited expression of AP-2α-regulated downstream genes. These array-based observations were further confirmed by microwell colorimetric TF assay and luciferase reporter assay. Downregulated transcription activity of AP-2α by Aurora-A was found to be associated with reduced AP-2α protein stability, which appeared to be mediated by Aurora-A enhanced ubiquitin-dependent proteasomal degradation of AP-2α protein. Interestingly, Aurora-A-mediated AP-2α degradation was likely dependent Aurora-A kinase activity since inhibition of Aurora-A kinase activity was able to rescue Aurora-A-induced degradation of AP-2α. Moreover, we defined a physical interaction between Aurora-A and AP-2α, and such interaction might bridge the suppressive effect of Aurora-A on AP-2α protein stability. These findings provide new insights into molecular mechanism by which Aurora-A acts as an oncogenic molecule in tumor occurrence and malignant development.
Highlights
Aurora-A is an important member of Aurora kinase family that includes Aurora-A, Aurora-B and Aurora-C
Human Aurora-A locates on chromosome 20q13, a region that is frequently amplified in primary breast tumors, colorectal cancers, ovarian cancers, neuroblastoma and multiple cancer cell lines[4,5]
AP-2a protein was seen in the pull-down complex by Aurora-A–GST, but not in the complex by GST protein (Figure 5C). These results indicate that there is a physical interaction between Aurora-A and AP-2a. Both of expression level and the kinase activity of Aurora kinases are found to be up-regulated in several human cancers, which are often companied by Aurora-A gene amplification[6,38]
Summary
Aurora-A is an important member of Aurora kinase family that includes Aurora-A, Aurora-B and Aurora-C This serine/threonine protein kinase family plays critical roles in the control of centrosome separation, bipolar spindle assembly, chromosome segregation and cytokinesis[1,2,3]. A number of investigations demonstrate that Aurora-A is overexpressed in human esophageal squamous cell carcinoma (ESCC). Aurora-A promotes cancer cell proliferation and inhibits cisplatin- or UV-induced apoptosis, probably through its up-regulation of Bcl-2 expression[7]. These observations strongly suggest that Aurora-A is dysregulated in human ESCC and plays an important role in the development of ESCC further investigations are required for elucidating the underlying mechanism
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