論文 - 詳細
| RRC ID | 60864 |
|---|---|
| 著者 | Morita K, He S, Nowak RP, Wang J, Zimmerman MW, Fu C, Durbin AD, Martel MW, Prutsch N, Gray NS, Fischer ES, Look AT. |
| タイトル | Allosteric Activators of Protein Phosphatase 2A Display Broad Antitumor Activity Mediated by Dephosphorylation of MYBL2. |
| ジャーナル | Cell |
| Abstract |
Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class of small-molecule iHAPs (improved heterocyclic activators of PP2A) that kill leukemia cells by allosterically assembling a specific heterotrimeric PP2A holoenzyme consisting of PPP2R1A (scaffold), PPP2R5E (B56ε, regulatory), and PPP2CA (catalytic) subunits. One compound, iHAP1, activates this complex but does not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase. In contrast, SMAPs, a separate class of compounds, activate PP2A holoenzymes containing a different regulatory subunit, do not dephosphorylate MYBL2, and arrest tumor cells in G1 phase. Our findings demonstrate that small molecules can serve as allosteric switches to activate distinct PP2A complexes with unique substrates. |
| 巻・号 | 181(3) |
| ページ | 702-715.e20 |
| 公開日 | 2020-4-30 |
| DOI | 10.1016/j.cell.2020.03.051 |
| PII | S0092-8674(20)30344-5 |
| PMID | 32315619 |
| PMC | PMC7397863 |
| MeSH | Apoptosis Cell Cycle Proteins / drug effects Cell Cycle Proteins / metabolism Cell Line, Tumor Enzyme Activators / metabolism G1 Phase Humans Multiprotein Complexes / metabolism Multiprotein Complexes / physiology Phenothiazines / pharmacology Phosphorylation Protein Phosphatase 2 / metabolism* Protein Phosphatase 2 / physiology Protein Subunits / metabolism Trans-Activators / drug effects Trans-Activators / metabolism Transcription Factors / metabolism |
| IF | 36.216 |
| 引用数 | 2 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 56 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | CSII-EF-MCS-IRES2-Venus (RDB04384) CSII-EF-MCS-IRES2-hKO1 (RDB07915) pENTR4-H1tetOx1 (RDB07916) CS-RfA-ETBsd (RDB07917) |