Enhanced Arginine Methylation of Programmed Cell Death 4 Protein during Nutrient Deprivation Promotes Tumor Cell Viability

• Published in: The Journal of biological chemistry Vol. 289; no. 25; pp. 17541 - 17552
• Main Authors: Fay, Marta M., Clegg, James M., Uchida, Kimberly A., Powers, Matthew A., Ullman, Katharine S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.06.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Apoptosis Regulatory Proteins - biosynthesis; Apoptosis Regulatory Proteins - genetics; Arginine - genetics; Arginine - metabolism; Cell Line, Tumor; Cell Survival - genetics; eIF4A; Gene Expression Regulation, Neoplastic; Humans; Methylation; Molecular Bases of Disease; Molecular Cell Biology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Nutrient Deprivation; Oncogene; PDCD4; Phosphorylation - genetics; PRMT5; Protein Methylation; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; RNA-Binding Proteins - biosynthesis; RNA-Binding Proteins - genetics; Translation Initiation Factor; Tumor Cell Biology; Tumor Suppressor Gene; Up-Regulation - genetics; Protein Methylation; Translation Initiation Factor; PRMT5; Tumor Cell Biology; Nutrient Deprivation; Molecular Cell Biology; Oncogene; PDCD4; Tumor Suppressor Gene; eIF4A
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.541300

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. Background: Elevated levels of both tumor suppressor PDCD4 and arginine methyltransferase PRMT5 correspond to aggressive tumor growth. Results: Nutrient deprivation increases methylated PDCD4, enhancing its interaction with eIF4A and promoting cell viability. Conclusion: Methylation of PDCD4 is responsive to the cellular metabolic state and promotes cell survival. Significance: PRMT5 controls PDCD4 in a context-dependent fashion to enhance tumor cell viability.