UBE3A /E6-AP regulates cell proliferation by promoting proteasomal degradation of p27

• Published in: Neurobiology of disease 2009-10, Vol.36 (1), p.26-34
• Main Authors: Mishra, Amit, Godavarthi, Swetha K, Jana, Nihar Ranjan
• Format: Article
• Language: English
• Subjects: Angelman syndrome; Animals; Apoptosis - drug effects; Apoptosis - genetics; Brain - cytology; Brain - metabolism; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Cells, Cultured; Cercopithecus aethiops; COS Cells; Cycloheximide - pharmacology; E6-AP; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Immunoprecipitation - methods; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroblastoma; Neurology; Neurons - metabolism; p27; Proliferating Cell Nuclear Antigen - genetics; Proliferating Cell Nuclear Antigen - metabolism; Proteasome; Protein Synthesis Inhibitors - pharmacology; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Transfection - methods; UBE3A; Ubiquitin ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - drug effects; Ubiquitination - genetics
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2009.06.010

Abstract 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.