p53 Protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation.

Abstract

Although p53 is frequently mutated in human cancers, about 80% of human melanomas retain wild-type p53. Here we report that PHGDH, the key metabolic enzyme that catalyzes the rate-limiting step of the serine biosynthesis pathway, is a target of p53 in human melanoma cells. p53 suppresses PHGDH expression and inhibits de novo serine biosynthesis. Notably, upon serine starvation, p53-mediated cell death is enhanced dramatically in response to Nutlin-3 treatment. Moreover, PHGDH has been found recently to be amplified frequently in human melanomas. We found that PHGDH overexpression significantly suppresses the apoptotic response, whereas RNAi-mediated knockdown of endogenous PHGDH promotes apoptosis under the same treatment. These results demonstrate an important role of p53 in regulating the serine biosynthesis pathway through suppressing PHGDH expression and reveal serine deprivation as a novel approach to sensitize p53-mediated apoptotic responses in human melanoma cells.

• Authors: Yang Ou, Shang-Jui Wang, Le Jiang, Bin Zheng, Wei Gu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 1 Pg. 457-66 (Jan 02 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 25404730 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• ATF4 protein, human
• Antineoplastic Agents
• Imidazoles
• Piperazines
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• Activating Transcription Factor 4
• Serine
• nutlin 3
• Phosphoglycerate Dehydrogenase

Topics

• Activating Transcription Factor 4 (antagonists & inhibitors, genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Base Sequence
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Imidazoles (pharmacology)
• Melanocytes (drug effects, metabolism, pathology)
• Molecular Sequence Data
• Phosphoglycerate Dehydrogenase (antagonists & inhibitors, genetics, metabolism)
• Piperazines (pharmacology)
• RNA, Small Interfering (genetics, metabolism)
• Serine (biosynthesis, deficiency)
• Signal Transduction
• Tumor Suppressor Protein p53 (antagonists & inhibitors, genetics, metabolism)