Enhanced arginine methylation of programmed cell death 4 protein during nutrient deprivation promotes tumor cell viability.
The role of programmed cell death 4 (PDCD4) in tumor biology is context-dependent. PDCD4 is described as a tumor suppressor, but its coexpression with protein arginine methyltransferase 5 (PRMT5) promotes accelerated tumor growth. Here, we report that PDCD4 is methylated during nutrient deprivation. Methylation occurs because of increased stability of PDCD4 protein as well as increased activity of PRMT5 toward PDCD4. During nutrient deprivation, levels of methylated PDCD4 promote cell viability, which is dependent on an enhanced interaction with eIF4A. Upon recovery from nutrient deprivation, levels of methylated PDCD4 are regulated by phosphorylation, which controls both the localization and stability of methylated PDCD4. This study reveals that, in response to particular environmental cues, the role of PDCD4 is up-regulated and is advantageous for cell viability. These findings suggest that the methylated form of PDCD4 promotes tumor viability during nutrient deprivation, ultimately allowing the tumor to grow more aggressively.
From the Oncological Sciences Department, Huntsman Cancer Institute and.
Marta M
MM
Fay
From the Oncological Sciences Department, Huntsman Cancer Institute and.
James M
JM
Clegg
From the Oncological Sciences Department, Huntsman Cancer Institute and Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112.
Kimberly A
KA
Uchida
From the Oncological Sciences Department, Huntsman Cancer Institute and.
Matthew A
MA
Powers
From the Oncological Sciences Department, Huntsman Cancer Institute and katie.ullman@hci.utah.edu.
Katharine S
KS
Ullman
D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008745:Methylation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D001120:Arginine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases
Molecular Cell Biology; Nutrient Deprivation; Oncogene; PDCD4; PRMT5; Protein Methylation; Translation Initiation Factor; Tumor Cell Biology; Tumor Suppressor Gene; eIF4A