PRMT4-Mediated Arginine Methylation Negatively Regulates Retinoblastoma Tumor Suppressor Protein and Promotes E2F-1 Dissociation
| Autor: | Bogdan Shevchenko, Mel Campbell, Chie Izumiya, Don Hong Wang, Steve B. Huerta, Kevin Y. Kim, Yoshihiro Izumiya |
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| Rok vydání: | 2015 |
| Předmět: |
Protein Structure
Protein-Arginine N-Methyltransferases Arginine 1.1 Normal biological development and functioning Retinoblastoma Protein Methylation Medical and Health Sciences Cell Line Underpinning research Cyclin-dependent kinase Cell Line Tumor Genetics Humans 2.1 Biological and endogenous factors Phosphorylation Aetiology E2F neoplasms Molecular Biology Protein Processing Regulation of gene expression Tumor biology Cell Cycle Post-Translational Retinoblastoma protein Articles Cell Biology Biological Sciences Cell cycle Molecular biology Recombinant Proteins Protein Structure Tertiary HEK293 Cells Gene Expression Regulation Mutation biology.protein biological phenomena cell phenomena and immunity Protein Processing Post-Translational Tertiary E2F1 Transcription Factor Developmental Biology |
| Zdroj: | Molecular and cellular biology, vol 35, iss 1 |
| ISSN: | 1098-5549 |
| Popis: | The retinoblastoma protein (pRb/p105) tumor suppressor plays a pivotal role in cell cycle regulation by blockage of the G1-to-S-phase transition. pRb tumor suppressor activity is governed by a variety of posttranslational modifications, most notably phosphorylation by cyclin-dependent kinase (Cdk) complexes. Here we report a novel regulation of pRb through protein arginine methyltransferase 4 (PRMT4)-mediated arginine methylation, which parallels phosphorylation. PRMT4 specifically methylates pRb at the pRb C-terminal domain (pRb C(term)) on arginine (R) residues R775, R787, and R798 in vitro and R787 in vivo. Arginine methylation is important for efficient pRb C(term) phosphorylation, as manifested by the reduced phosphorylation of a methylation-impaired mutant, pRb (R3K). A methylmimetic form of pRb, pRb (R3F), disrupts the formation of the E2F-1/DP1-pRb complex in cells as well as in an isolated system. Finally, studies using a Gal4-E2F-1 reporter system show that pRb (R3F) expression reduces the ability of pRb to repress E2F-1 transcriptional activation, while pRb (R3K) expression further represses E2F-1 transcriptional activation relative to that for cells expressing wild-type pRb. Together, our results suggest that arginine methylation negatively regulates the tumor suppressor function of pRb during cell cycle control, in part by creating a better substrate for Cdk complex phosphorylation and disrupting the interaction of pRb with E2F-1. |
| Databáze: | OpenAIRE |
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