Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase.
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 coregulatory 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 rereplication. Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity.
Aggarwal
Priya
P
Abramson Family Cancer Research Institute, Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, 19104, USA.
Vaites
Laura Pontano
LP
Kim
Jong Kyong
JK
Mellert
Hestia
H
Gurung
Buddha
B
Nakagawa
Hiroshi
H
Herlyn
Meenhard
M
Hua
Xianxin
X
Rustgi
Anil K
AK
McMahon
Steven B
SB
Diehl
J Alan
JA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology*; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D019175:DNA Methylation; D004261:DNA Replication; D004789:Enzyme Activation; D044783:F-Box Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008223:Lymphoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000378:metabolism*; D055550:Protein Stability; D014157:Transcription Factors
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D044783:F-Box Proteins; D006657:Histones; D011496:Protein Methyltransferases; C467199:CDT1 protein, human; C515213:Fbx4 protein, mouse; C478359:WDR77 protein, human; D014157:Transcription Factors