A p53-inducible microRNA-34a downregulates Ras signaling by targeting IMPDH.
p53 is a well-known transcription factor that controls cell cycle arrest and cell death in response to a wide range of stresses. Moreover, p53 regulates glucose metabolism and its mutation results in the metabolic switch to the Warburg effect found in cancer cells. Nucleotide biosynthesis is also critical for cell proliferation and the cell division cycle. Nonetheless, little is known about whether p53 regulates nucleotide biosynthesis. Here we demonstrated that p53-inducible microRNA-34a (miR-34a) repressed inosine 5'-monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme of de novo GTP biosynthesis. Treatment with anti-miR-34a inhibitor relieved the expression of IMPDH upon DNA damage. Ultimately, miR-34a-mediated inhibition of IMPDH resulted in repressed activation of the GTP-dependent Ras signaling pathway. In summary, we suggest that p53 has a novel function in regulating purine biosynthesis, aided by miR-34a-dependent IMPDH repression.
National Research Laboratory for Metabolic Checkpoint, Departments of Biomedical Sciences and Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
Hwa-Ryeon
HR
Kim
Jae-Seok
JS
Roe
Ji-Eun
JE
Lee
In-Young
IY
Hwang
Eun-Jung
EJ
Cho
Hong-Duk
HD
Youn
D004249:DNA Damage; D015536:Down-Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D018631:ras Proteins