UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27.
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.
Mishra
Amit
A
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon-122 050, India.
Godavarthi
Swetha K
SK
Jana
Nihar Ranjan
NR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000378:metabolism; D019556:COS Cells; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics
D018809:Proliferating Cell Nuclear Antigen; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C413374:p27 antigen; D003513:Cycloheximide; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases