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- W4361243501 abstract "<div>Abstract<p>The cell cycle regulator, SKP2, is overexpressed in various cancers and plays a key role in p27 degradation, which is involved in tumor cell dedifferentiation. Little is known about the mechanisms leading to impaired <i>SKP2</i> transcriptional control in tumor cells. We used neuroblastoma as a model to study <i>SKP2</i> regulation because <i>SKP2</i> transcript levels gradually increase with aggressiveness of neuroblastoma subtypes. The highest <i>SKP2</i> levels are found in neuroblastomas with amplified <i>MYCN</i>. Accordingly, we found 5.5-fold (range, 2–9.5) higher <i>SKP2</i> core promoter activity in <i>MYCN</i>-amplified cells. Higher <i>SKP2</i> core promoter activity in <i>MYCN</i>-amplified cells is mediated through a defined region at the transcriptional start site. This region includes a specific E2F-binding site that makes <i>SKP2</i> activation largely independent of mitogenic signals integrated through the SP1/ELK-1 site. We show by chromatin immunoprecipitation that <i>SKP2</i> activation through the transcriptional start site in <i>MYCN</i>-amplified cells is associated with the low abundance of pRB-E2F1 complexes bound to the <i>SKP2</i> promoter. Transcriptional control of <i>SKP2</i> through this regulatory mechanism can be reestablished in <i>MYCN</i>-amplified cells by restoring pRB activity using selective small compound inhibitors of CDK4. In contrast, doxorubicin or nutlin-3 treatment—both leading to p53-p21 activation—or CDK2 inhibition had no effect on SKP2 regulation in <i>MYCN</i>-amplified cells. Together, this implies that deregulated MYCN protein levels in <i>MYCN</i>-amplified neuroblastoma cells activate <i>SKP2</i> through <i>CDK4</i> induction, abrogating repressive pRB-E2F1 complexes bound to the <i>SKP2</i> promoter. Cancer Res; 70(9); 3791–802. ©2010 AACR.</p></div>" @default.
- W4361243501 created "2023-03-31" @default.
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- W4361243501 date "2023-03-30" @default.
- W4361243501 modified "2023-10-16" @default.
- W4361243501 title "Data from Transcriptional Repression of <i>SKP2</i> Is Impaired in <i>MYCN</i>-Amplified Neuroblastoma" @default.
- W4361243501 doi "https://doi.org/10.1158/0008-5472.c.6500168" @default.
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