Mycophenolic acid activation of p53 requires ribosomal proteins L5 and L11.
Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is widely used as an immunosuppressive agent. MPA selectively inhibits inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme for the de novo synthesis of guanine nucleotides, leading to depletion of the guanine nucleotide pool. Its chemotherapeutic effects have been attributed to its ability to induce cell cycle arrest and apoptosis. MPA treatment has also been shown to induce and activate p53. However, the mechanism underlying the p53 activation pathway is still unclear. Here, we show that MPA treatment results in inhibition of pre-rRNA synthesis and disruption of the nucleolus. This treatment enhances the interaction of MDM2 with L5 and L11. Interestingly, knockdown of endogenous L5 or L11 markedly impairs the induction of p53 and G(1) cell cycle arrest induced by MPA. These results suggest that MPA may trigger a nucleolar stress that induces p53 activation via inhibition of MDM2 by ribosomal proteins L5 and L11.
Sun
Xiao-Xin
XX
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Simon Cancer Center, Indianapolis, Indiana 46202, USA.
Dai
Mu-Shui
MS
Lu
Hua
H
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006150:Guanine Nucleotides / Q000172:deficiency; D006801:Humans; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012322:RNA Precursors / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D006150:Guanine Nucleotides; D009687:Nuclear Proteins; D012322:RNA Precursors; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; C029742:ribosomal protein L5; D000090243:Nucleophosmin; D051736:Proto-Oncogene Proteins c-mdm2; D009173:Mycophenolic Acid