Oncogene database

10419

PRMT5

protein arginine methyltransferase 5;PRMT5;protein arginine methyltransferase 5

72 kDa ICln-binding protein|HMT1 hnRNP methyltransferase-like 5|SKB1 homolog|histone-arginine N-methyltransferase PRMT5|jak-binding protein 1|protein arginine N-methyltransferase 5|shk1 kinase-binding protein 1 homolog

14q11.2

protein-coding

A Janus-2 (JAK-2) binding protein, JBP1, has been found to function as an arginine methyl transferase and is now designated PRMT5. Co-injection of plasmids encoding this protein together with oncogenic (Val 12-containing) ras-p21 protein into Xenopus leavis oocytes results in strong inhibition of oncogenic p21-induced oocyte maturation. This inhibition appears to be dependent on the methyl transferase function since a partially active R368A mutant shows diminished ability to inhibit Val 12-p21-induced oocyte maturation, and an almost totally inactive GAGRG (365-369) deletion mutant fails to inhibit Val 12-p21-induced maturation. In contrast, PRMT5 (JBP1) does not inhibit insulin-induced oocyte maturation. Since insulin-induced maturation depends on activation of cellular ras-p21, PRMT5 does not appear to inhibit the wild-type p21 protein. We also find that arginine methyl transferase inhibitors strongly block oncogenic ras-p21-activated, but not insulin-activated, wild-type ras-p21-induced oocyte maturation. Thus signaling by oncogenic p21 appears to involve methyltransferases uniquely. Surprisingly, the active site peptide, Gly-Arg-Gly, strongly suppresses insulin-induced maturation but has no effect on Val 12-p21-induced maturation. This peptide may therefore be useful in defining steps in the wild-type ras pathway.

Increasing evidence suggests that PRMT5, a protein arginine methyltransferase, is involved in tumorigenesis. However, no systematic research has demonstrated the cell-transforming activity of PRMT5. We investigated the involvement of PRMT5 in tumor formation. First, we showed that PRMT5 was associated with many human cancers, through statistical analysis of microarray data in the NCBI GEO database. Overexpression of ectopic PRMT5 per se or its specific shRNA enhanced or reduced cell growth under conditions of normal or low concentrations of serum, low cell density, and poor cell attachment. A stable clone that expressed exogenous PRMT5 formed tumors in nude mice, which demonstrated that PRMT5 is a potential oncoprotein. PRMT5 accelerated cell cycle progression through G1 phase and modulated regulators of G1; for example, it upregulated cyclin-dependent kinase (CDK) 4, CDK6, and cyclins D1, D2 and E1, and inactivated retinoblastoma protein (Rb). Moreover, PRMT5 activated phosphoinositide 3-kinase (PI3K)/AKT and suppressed c-Jun N-terminal kinase (JNK)/c-Jun signaling cascades. However, only inhibition of PI3K activity, and not overexpression of JNK, blocked PRMT5-induced cell proliferation. Further analysis of PRMT5 expression in 64 samples of human lung cancer tissues by microarray and western blot analysis revealed a tight association of PRMT5 with lung cancer. Knockdown of PRMT5 retarded cell growth of lung cancer cell lines A549 and H1299. In conclusion, to the best of our knowledge, we have characterized the cell-transforming activity of PRMT5 and delineated its underlying mechanisms for the first time.

Protein arginine methyltransferase 5 (PRMT5) has been implicated as a key modulator of lymphomagenesis. Whether PRMT5 has overt oncogenic function in the context of leukemia/lymphoma and whether it represents a therapeutic target remains to be established. We demonstrate that inactivation of PRMT5 inhibits colony-forming activity by multiple oncogenic drivers, including cyclin D1, c-MYC, NOTCH1, and MLL-AF9. Furthermore, we demonstrate that PRMT5 overexpression specifically cooperates with cyclin D1 to drive lymphomagenesis in a mouse model, revealing inherent neoplastic activity. Molecular analysis of lymphomas revealed that arginine methylation of p53 selectively suppresses expression of crucial proapoptotic and antiproliferative target genes, thereby sustaining tumor cell self-renewal and proliferation and bypassing the need for the acquisition of inactivating p53 mutations. Critically, analysis of human tumor specimens reveals a strong correlation between cyclin D1 overexpression and p53 methylation, supporting the biomedical relevance of this pathway. SIGNIFICANCE: We have identified and functionally validated a crucial role for PRMT5 for the inhibition of p53-dependent tumor suppression in response to oncogenic insults. The requisite role for PRMT5 in the context of multiple lymphoma/leukemia oncogenic drivers suggests a molecular rationale for therapeutic development.