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 c...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2009-10-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996109001594 |
| _version_ | 1819119820057083904 |
|---|---|
| author | Amit Mishra Swetha K. Godavarthi Nihar Ranjan Jana |
| author_facet | Amit Mishra Swetha K. Godavarthi Nihar Ranjan Jana |
| author_sort | Amit Mishra |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T06:10:50Z |
| format | Article |
| id | doaj.art-07dff4518a214a9b98aabc495657e3a9 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T06:10:50Z |
| publishDate | 2009-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-07dff4518a214a9b98aabc495657e3a92022-12-21T18:36:13ZengElsevierNeurobiology of Disease1095-953X2009-10-013612634UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27Amit Mishra0Swetha K. Godavarthi1Nihar Ranjan Jana2Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon-122 050, IndiaCellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon-122 050, IndiaCorresponding author. Fax: +91 124 2338910.; Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon-122 050, IndiaThe 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.http://www.sciencedirect.com/science/article/pii/S0969996109001594E6-APUBE3AProteasomep27Angelman syndromeCell cycle |
| spellingShingle | Amit Mishra Swetha K. Godavarthi Nihar Ranjan Jana UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27 Neurobiology of Disease E6-AP UBE3A Proteasome p27 Angelman syndrome Cell cycle |
| title | UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27 |
| title_full | UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27 |
| title_fullStr | UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27 |
| title_full_unstemmed | UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27 |
| title_short | UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27 |
| title_sort | ube3a e6 ap regulates cell proliferation by promoting proteasomal degradation of p27 |
| topic | E6-AP UBE3A Proteasome p27 Angelman syndrome Cell cycle |
| url | http://www.sciencedirect.com/science/article/pii/S0969996109001594 |
| work_keys_str_mv | AT amitmishra ube3ae6apregulatescellproliferationbypromotingproteasomaldegradationofp27 AT swethakgodavarthi ube3ae6apregulatescellproliferationbypromotingproteasomaldegradationofp27 AT niharranjanjana ube3ae6apregulatescellproliferationbypromotingproteasomaldegradationofp27 |