PRMT4-Mediated Arginine Methylation Negatively Regulates Retinoblastoma Tumor Suppressor Protein and Promotes E2F-1 Dissociation
Copyright policy )PRMT4-Mediated Arginine Methylation Negatively Regulates Retinoblastoma Tumor Suppressor Protein and Promotes E2F-1 Dissociation
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.
- University of California, Davis United States
- UC Davis Comprehensive Cancer Center United States
- University of California, San Francisco United States
Gene Expression Regulation (mesh), Protein-Arginine N-Methyltransferases, 11 Medical and Health Sciences (for), Medical and Health Sciences, Retinoblastoma Protein, 31 Biological sciences (for-2020), 2.1 Biological and endogenous factors, Phosphorylation, 32 Biomedical and Clinical Sciences (for-2020), Cell Cycle (mesh), Cancer, Post-Translational (mesh), Developmental Biology (science-metrix), Cancer (rcdc), Protein-Arginine N-Methyltransferases (mesh), Humans (mesh), Tumor, Mutation (mesh), Generic health relevance (hrcs-hc), Cell Cycle, Biological Sciences, Retinoblastoma Protein (mesh), Recombinant Proteins, 06 Biological Sciences (for), Tumor (mesh), E2F1 Transcription Factor (mesh), Arginine (mesh), 570, Protein Structure, Arginine, Methylation, Cell Line, 42 Health sciences (for-2020), Cell Line, Tumor, Genetics, Recombinant Proteins (mesh), Humans, Protein Processing, HEK293 Cells (mesh), 31 Biological Sciences (for-2020), Biomedical and Clinical Sciences, Genetics (rcdc), Phosphorylation (mesh), Post-Translational, Health sciences, 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), Methylation (mesh), 3101 Biochemistry and Cell Biology (for-2020), Protein Structure, Tertiary, Tertiary (mesh), HEK293 Cells, 32 Biomedical and clinical sciences (for-2020), Gene Expression Regulation, Mutation, Biochemistry and Cell Biology, Generic health relevance, Protein Processing, Post-Translational, Tertiary, E2F1 Transcription Factor, Developmental Biology
Gene Expression Regulation (mesh), Protein-Arginine N-Methyltransferases, 11 Medical and Health Sciences (for), Medical and Health Sciences, Retinoblastoma Protein, 31 Biological sciences (for-2020), 2.1 Biological and endogenous factors, Phosphorylation, 32 Biomedical and Clinical Sciences (for-2020), Cell Cycle (mesh), Cancer, Post-Translational (mesh), Developmental Biology (science-metrix), Cancer (rcdc), Protein-Arginine N-Methyltransferases (mesh), Humans (mesh), Tumor, Mutation (mesh), Generic health relevance (hrcs-hc), Cell Cycle, Biological Sciences, Retinoblastoma Protein (mesh), Recombinant Proteins, 06 Biological Sciences (for), Tumor (mesh), E2F1 Transcription Factor (mesh), Arginine (mesh), 570, Protein Structure, Arginine, Methylation, Cell Line, 42 Health sciences (for-2020), Cell Line, Tumor, Genetics, Recombinant Proteins (mesh), Humans, Protein Processing, HEK293 Cells (mesh), 31 Biological Sciences (for-2020), Biomedical and Clinical Sciences, Genetics (rcdc), Phosphorylation (mesh), Post-Translational, Health sciences, 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), Methylation (mesh), 3101 Biochemistry and Cell Biology (for-2020), Protein Structure, Tertiary, Tertiary (mesh), HEK293 Cells, 32 Biomedical and clinical sciences (for-2020), Gene Expression Regulation, Mutation, Biochemistry and Cell Biology, Generic health relevance, Protein Processing, Post-Translational, Tertiary, E2F1 Transcription Factor, Developmental Biology
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