Nuclear Cyclin D1/CDK4 Kinase Regulates CUL4 Expression and Triggers Neoplastic Growth via Activation of the PRMT5 Methyltransferase

Abstract

Summary Cyclin D1 elicits transcriptional effects through inactivation of the retinoblastoma protein and direct association with transcriptional regulators. The current work reveals a molecular relationship between cyclin D1/CDK4 kinase and protein arginine methyltransferase 5 (PRMT5), an enzyme associated with histone methylation and transcriptional repression. Primary tumors of a mouse lymphoma model exhibit increased PRMT5 methyltransferase activity and histone arginine methylation. Analyses demonstrate that MEP50, a PRMT5 co-regulatory factor, is a CDK4 substrate, and phosphorylation increases PRMT5/MEP50 activity. Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth including CUL4 repression, CDT1 overexpression, and DNA re-replication. Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity.

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G2/M phases of the cell cycle

“…Actually, a few other antibodies also result in similar data (not shown). Many published studies also show CDK4 as a duplet 22,39 or as multiple bands, 21 sometimes even expressed from a CDK4-HA construct, 26 although no comments are given. Our LC-MS/MS analysis confirms that some proteins below 33 kD are CDK4 isoforms, which likely lack part of the sequence.…”

Mediator Complex Recruits Epigenetic Regulators via Its Two Cyclin-dependent Kinase Subunits to Repress Transcription of Immune Response Genes

“…In the context of transcriptional regulation, histones are particularly well known targets of PRMT5-directed methylation (39,50,51). The association of PRMT5 with both CDK8 and CDK19 indicates that this histone-modifying enzyme has a close relationship with Mediator (Fig.…”

Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer

“…Because PRMT5 is implicated in diverse cellular and biological processes such as transcriptional regulation, RNA metabolism, ribosome biogenesis, Golgi apparatus homeostasis and cell cycle regulation, PRMT5 is generating increased interest in the field of cancer research (12,15,16). For example, PRMT5 is expressed at higher levels compared with normal tissues in leukemias, lymphomas and gliomas as well as in ovarian, breast, prostate and lung cancers (13,14,(17)(18)(19)(20).…”