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Mishra A, Godavarthi SK, Jana NR: UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27. Neurobiol Dis. 2009 Oct;36(1):26-34. Epub 2009 Jul 8.
The UBE3A/E6-AP is known to function both as an E3 ubiquitin ligase of the ubiquitin proteasome system and as a transcriptional coactivator. E6-AP shows brain-specific imprinting and loss of function of maternally inherited E6-AP causes Angelman syndrome. However, how the loss of function of E6-AP causes disease pathogenesis is poorly understood. Here, we show that E6-AP interacts with and promotes proteasome-mediated degradation of cyclin-dependent kinase inhibitor p27. E6-AP also directly ubiquitinates p27 in an in vitro ubiquitination assay. Partial knockdown of E6-AP increases the level of p27 leading to cell cycle arrest. Interestingly, partial knockdown also increases the transcription of p27. Finally, we have demonstrated the increased levels of p27 in E6-AP-maternal-deficient and null mice brain. Our result suggests that E6-AP not only enhances the degradation but also regulates the expression of p27 and its loss of function in Angelman syndrome might cause cell cycle alteration leading to disease pathogenesis. |
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