Ribosomal Protein L23 Activates P53 by Inhibiting MDM2 Function in Response to Ribosomal Perturbation but Not to Translation Inhibition

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2004 Aug 18

PMID 15314173

Citations 265

Authors

Mu-Shui Dai

Shelya X Zeng

Yetao Jin

Xiao-Xin Sun

Larry David

Hua Lu

Affiliations

Soon will be listed here.

Abstract

The p53-MDM2 feedback loop is vital for cell growth control and is subjected to multiple regulations in response to various stress signals. Here we report another regulator of this loop. Using an immunoaffinity method, we purified an MDM2-associated protein complex that contains the ribosomal protein L23. L23 interacted with MDM2, forming a complex independent of the 80S ribosome and polysome. The interaction of L23 with MDM2 was enhanced by treatment with actinomycin D but not by gamma-irradiation, leading to p53 activation. This activation was inhibited by small interfering RNA against L23. Ectopic expression of L23 reduced MDM2-mediated p53 ubiquitination and also induced p53 activity and G(1) arrest in p53-proficient U2OS cells but not in p53-deficient Saos-2 cells. These results reveal that L23 is another regulator of the p53-MDM2 feedback regulation.

Citing Articles

Tripartite motif-containing protein 26 promotes colorectal cancer growth by inactivating p53.

Tan Z, Ko H, Naji P, Zhu R, Wang J, Huang S Cell Death Differ. 2025; .

PMID: 39994352 DOI: 10.1038/s41418-025-01463-1.

TP53 mutations and MDM2 polymorphisms in breast and ovarian cancers: amelioration by drugs and natural compounds.

Chakraborty R, Dutta A, Mukhopadhyay R Clin Transl Oncol. 2025; .

PMID: 39797946 DOI: 10.1007/s12094-024-03841-6.

The Influence of Extra-Ribosomal Functions of Eukaryotic Ribosomal Proteins on Viral Infection.

Zhao Z, Ruan S, Li Y, Qi T, Qi Y, Huang Y Biomolecules. 2025; 14(12.

PMID: 39766272 PMC: 11674327. DOI: 10.3390/biom14121565.

Explore the expression of mitochondria-related genes to construct prognostic risk model for ovarian cancer and validate it, so as to provide optimized treatment for ovarian cancer.

Yunyun Z, Guihu W, An J Front Immunol. 2024; 15:1458264.

PMID: 39478854 PMC: 11521951. DOI: 10.3389/fimmu.2024.1458264.

USP36 SUMOylates Las1L and Promotes Its Function in Pre-Ribosomal RNA ITS2 Processing.

Li Y, Yang Y, Sears R, Dai M, Sun X Cancer Res Commun. 2024; 4(10):2835-2845.

PMID: 39356143 PMC: 11523043. DOI: 10.1158/2767-9764.CRC-24-0312.

References

Jin Y, Zeng S, Dai M, Yang X, Lu H . MDM2 inhibits PCAF (p300/CREB-binding protein-associated factor)-mediated p53 acetylation. J Biol Chem. 2002; 277(34):30838-43. DOI: 10.1074/jbc.M204078200. View

Zeng S, Dai M, Keller D, Lu H . SSRP1 functions as a co-activator of the transcriptional activator p63. EMBO J. 2002; 21(20):5487-97. PMC: 129072. DOI: 10.1093/emboj/cdf540. View

Tsai R, McKay R . A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev. 2002; 16(23):2991-3003. PMC: 187487. DOI: 10.1101/gad.55671. View

Oren M, Damalas A, Gottlieb T, Michael D, Taplick J, Martinez Leal J . Regulation of p53: intricate loops and delicate balances. Ann N Y Acad Sci. 2002; 973:374-83. DOI: 10.1111/j.1749-6632.2002.tb04669.x. View

Ruggero D, Grisendi S, Piazza F, Rego E, Mari F, Rao P . Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science. 2003; 299(5604):259-62. DOI: 10.1126/science.1079447. View

Nikolaev A, Li M, Puskas N, Qin J, Gu W . Parc: a cytoplasmic anchor for p53. Cell. 2003; 112(1):29-40. DOI: 10.1016/s0092-8674(02)01255-2. View

Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S . The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell. 2003; 112(3):317-27. DOI: 10.1016/s0092-8674(03)00079-5. View

Ruggero D, Pandolfi P . Does the ribosome translate cancer?. Nat Rev Cancer. 2003; 3(3):179-92. DOI: 10.1038/nrc1015. View

Sugimoto M, Kuo M, Roussel M, Sherr C . Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing. Mol Cell. 2003; 11(2):415-24. DOI: 10.1016/s1097-2765(03)00057-1. View

10.

Lohrum M, Ludwig R, Kubbutat M, Hanlon M, Vousden K . Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell. 2003; 3(6):577-87. DOI: 10.1016/s1535-6108(03)00134-x. View

11.

Zhang Y, White Wolf G, Bhat K, Jin A, Allio T, Burkhart W . Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol. 2003; 23(23):8902-12. PMC: 262682. DOI: 10.1128/MCB.23.23.8902-8912.2003. View

12.

Jin Y, Lee H, Zeng S, Dai M, Lu H . MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. EMBO J. 2003; 22(23):6365-77. PMC: 291841. DOI: 10.1093/emboj/cdg600. View

13.

Lane D, Harlow E . Two different viral transforming proteins bind the same host tumour antigen. Nature. 1982; 298(5874):517. DOI: 10.1038/298517a0. View

14.

Geyer R, Yu Z, Maki C . The MDM2 RING-finger domain is required to promote p53 nuclear export. Nat Cell Biol. 2000; 2(9):569-73. DOI: 10.1038/35023507. View

15.

Boyd M, Vlatkovic N, Haines D . A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that is suppressed by MDM2. J Biol Chem. 2000; 275(41):31883-90. DOI: 10.1074/jbc.M004252200. View

16.

Kobet E, Zeng X, Zhu Y, Keller D, Lu H . MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins. Proc Natl Acad Sci U S A. 2000; 97(23):12547-52. PMC: 18801. DOI: 10.1073/pnas.97.23.12547. View

17.

Vogelstein B, Lane D, Levine A . Surfing the p53 network. Nature. 2000; 408(6810):307-10. DOI: 10.1038/35042675. View

18.

Zeng X, Lee H, Zhang Q, Lu H . p300 does not require its acetylase activity to stimulate p73 function. J Biol Chem. 2000; 276(1):48-52. DOI: 10.1074/jbc.C000722200. View

19.

Matsutake T, Srivastava P . The immunoprotective MHC II epitope of a chemically induced tumor harbors a unique mutation in a ribosomal protein. Proc Natl Acad Sci U S A. 2001; 98(7):3992-7. PMC: 31167. DOI: 10.1073/pnas.071523398. View

20.

Maya R, Balass M, Kim S, Shkedy D, Leal J, Shifman O . ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev. 2001; 15(9):1067-77. PMC: 312683. DOI: 10.1101/gad.886901. View