Protein arginine methyltransferase 5 is a potential oncoprotein that upregulatesG1 cyclins/cyclin‐dependent kinases and the phosphoinositide 3‐kinase/AKTsignaling cascade

Abstract

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.

Evolutionary Emergence of a Novel Splice Variant with an Opposite Effect on the Cell Cycle

“…This change is consistent with the predominant expression of PRMT5L in HeLa cells (Fig. 2C and 4B) and its mitosis-promoting effect (41,(44)(45)(46)61). Importantly, as anticipated, rescue with MycPRMT5L significantly reduced the proportion of interphase cells to 28.7% (Ϯ6.6%, P ϭ 0.002) (Fig.…”

“…Consistent with the known function of PRMT5 in promoting cell proliferation (41,(44)(45)(46)61), PRMT5L-preferred genes were significantly enriched in functional clusters of cell growth and proliferation. Strikingly, the functions of the 50 PRMT5S-preferred genes clustered most significantly in cell death and cell cycle arrest pathways (Fig.…”

“…To determine the effect of the PRMT5S protein on cells, we examined it during the cell cycle, where PRMT5L plays an important role (41,(44)(45)(46)61). We differentiated the interphase and mitotic phases by the typical tubulin and DAPI staining patterns in HeLa cells that had been left untreated (control), subjected to PRMT5 knockdown (shPRMT5), or rescued with either one of the splice variants (Fig.…”

“…It controls gene transcription/RNA processing (32,(38)(39)(40), maintains circadian rhythm and stem cell pluripotency or proliferation (34,(40)(41)(42)(43), accelerates cell cycle progression (44,45), and promotes tumorigenesis (37,46). However, the molecular basis of these diverse roles in cellular processes has not been fully understood.…”

Elevated expression of protein arginine methyltransferase 5 predicts the poor prognosis of breast cancer

“…14 Increased proliferation, induced anchorage-independent colony growth, as well as tumorigenesis were found when PRMT5 is overexpressed; therefore, PRMT5 has been considered a promising target for cancer therapy. [15][16][17] Recently, several studies indicated that PRMT5 plays important roles in breast tumorigenesis. [18][19][20][21] It is reported that PRMT5 binds to the zinc finger structures in tumor necrosis factor receptor-associated factor 4 (TRAF4) and is regulated by this scaffold protein; TRAF4 participates in nuclear factor (NF)-κB signaling and is involved in the promotion of cell proliferation and survival in breast cancer.…”