Cancer-associated mutations in the ribosomal protein L5 gene dysregulate the HDM2/p53-mediated ribosome biogenesis checkpoint

Oncogene ◽  
2020 ◽  
Vol 39 (17) ◽  
pp. 3443-3457 ◽  
Author(s):  
Ines Oršolić ◽  
Slađana Bursać ◽  
Deana Jurada ◽  
Irena Drmić Hofman ◽  
Zlatko Dembić ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Ribosomal Protein L5

scholarly journals Nucleophosmin Is Essential for Ribosomal Protein L5 Nuclear Export

2006 ◽  
Vol 26 (10) ◽  
pp. 3798-3809 ◽  
Author(s):  
Yue Yu ◽  
Leonard B. Maggi ◽  
Suzanne N. Brady ◽  
Anthony J. Apicelli ◽  
Mu-Shui Dai ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Nuclear Export ◽  
Ribosome Biogenesis ◽  
Protein Complexes ◽  
Direct Interaction ◽  
5S Rrna ◽  
Centrosome Duplication ◽  
Ribosomal Subunits ◽  
Cycle Arrest ◽  
Ribosomal Protein L5

ABSTRACT Nucleophosmin (NPM/B23) is a key regulator in the regulation of a number of processes including centrosome duplication, maintenance of genomic integrity, and ribosome biogenesis. While the mechanisms underlying NPM function are largely uncharacterized, NPM loss results in severe dysregulation of developmental and growth-related events. We show that NPM utilizes a conserved CRM1-dependent nuclear export sequence in its amino terminus to enable its shuttling between the nucleolus/nucleus and cytoplasm. In search of NPM trafficking targets, we biochemically purified NPM-bound protein complexes from HeLa cell lysates. Consistent with NPM's proposed role in ribosome biogenesis, we isolated ribosomal protein L5 (rpL5), a known chaperone for the 5S rRNA. Direct interaction of NPM with rpL5 mediated the colocalization of NPM with maturing nuclear 60S ribosomal subunits, as well as newly exported and assembled 80S ribosomes and polysomes. Inhibition of NPM shuttling or loss of NPM blocked the nuclear export of rpL5 and 5S rRNA, resulting in cell cycle arrest and demonstrating that NPM and its nuclear export provide a unique and necessary chaperoning activity to rpL5/5S.

scholarly journals Ribosome Biogenesis in African Trypanosomes Requires Conserved and Trypanosome-Specific Factors

2014 ◽  
Vol 13 (6) ◽  
pp. 727-737 ◽  
Author(s):  
Khan Umaer ◽  
Martin Ciganda ◽  
Noreen Williams
Keyword(s):  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Large Subunit ◽  
Ribosomal Subunit ◽  
Small Subunit ◽  
5S Rrna ◽  
Content Type ◽  
African Trypanosomes ◽  
Ribosomal Protein L5

ABSTRACTLarge ribosomal subunit protein L5 is responsible for the stability and trafficking of 5S rRNA to the site of eukaryotic ribosomal assembly. InTrypanosoma brucei, in addition to L5, trypanosome-specific proteins P34 and P37 also participate in this process. These two essential proteins form a novel preribosomal particle through interactions with both the ribosomal protein L5 and 5S rRNA. We have generated a procyclic L5 RNA interference cell line and found that L5 itself is a protein essential for trypanosome growth, despite the presence of other 5S rRNA binding proteins. Loss of L5 decreases the levels of all large-subunit rRNAs, 25/28S, 5.8S, and 5S rRNAs, but does not alter small-subunit 18S rRNA. Depletion of L5 specifically reduced the levels of the other large ribosomal proteins, L3 and L11, whereas the steady-state levels of the mRNA for these proteins were increased. L5-knockdown cells showed an increase in the 40S ribosomal subunit and a loss of the 60S ribosomal subunits, 80S monosomes, and polysomes. In addition, L5 was involved in the processing and maturation of precursor rRNAs. Analysis of polysomal fractions revealed that unprocessed rRNA intermediates accumulate in the ribosome when L5 is depleted. Although we previously found that the loss of P34 and P37 does not result in a change in the levels of L5, the loss of L5 resulted in an increase of P34 and P37 proteins, suggesting the presence of a compensatory feedback loop. This study demonstrates that ribosomal protein L5 has conserved functions, in addition to nonconserved trypanosome-specific features, which could be targeted for drug intervention.

scholarly journals Molecular cloning and nucleotide sequence of cDNA specific for rat ribosomal protein L5

1987 ◽  
Vol 168 (1) ◽  
pp. 83-87 ◽  
Author(s):  
Satoru TAMURA ◽  
Yuh KUWANO ◽  
Tatsuo NAKAYAMA ◽  
Shoji TANAKA ◽  
Tatsuo TANAKA ◽  
...  
Keyword(s):  
Nucleotide Sequence ◽  
Ribosomal Protein ◽  
Molecular Cloning ◽  
Ribosomal Protein L5

scholarly journals Ribosomal Protein S6 Gene Haploinsufficiency Is Associated with Activation of a p53-Dependent Checkpoint during Gastrulation

2006 ◽  
Vol 26 (23) ◽  
pp. 8880-8891 ◽  
Author(s):  
Linda Panić ◽  
Sanda Tamarut ◽  
Melanie Sticker-Jantscheff ◽  
Martina Barkić ◽  
Davor Solter ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Embryonic Development ◽  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Fetal Liver ◽  
Genetic Inactivation ◽  
Developmental Program ◽  
Ribosomal Protein S6 ◽  
M Phase ◽  
Insight Into

ABSTRACT Nascent ribosome biogenesis is required during cell growth. To gain insight into the importance of this process during mouse oogenesis and embryonic development, we deleted one allele of the ribosomal protein S6 gene in growing oocytes and generated S6-heterozygous embryos. Oogenesis and embryonic development until embryonic day 5.5 (E5.5) were normal. However, inhibition of entry into M phase of the cell cycle and apoptosis became evident post-E5.5 and led to perigastrulation lethality. Genetic inactivation of p53 bypassed this checkpoint and prolonged development until E12.5, when the embryos died, showing decreased expression of D-type cyclins, diminished fetal liver erythropoiesis, and placental defects. Thus, a p53-dependent checkpoint is activated during gastrulation in response to ribosome insufficiency to prevent improper execution of the developmental program.

scholarly journals Perturbation of 60 S Ribosomal Biogenesis Results in Ribosomal Protein L5- and L11-dependent p53 Activation

2010 ◽  
Vol 285 (33) ◽  
pp. 25812-25821 ◽  
Author(s):  
Xiao-Xin Sun ◽  
Yue-Gang Wang ◽  
Dimitris P. Xirodimas ◽  
Mu-Shui Dai
Keyword(s):  
Ribosomal Protein ◽  
Ribosomal Biogenesis ◽  
P53 Activation ◽  
Ribosomal Protein L5

Mutual Induced Fit Binding of Xenopus Ribosomal Protein L5 to 5S rRNA

2003 ◽  
Vol 330 (5) ◽  
pp. 979-992 ◽  
Author(s):  
Jonathan P. DiNitto ◽  
Paul W. Huber
Keyword(s):  
Ribosomal Protein ◽  
5S Rrna ◽  
Induced Fit ◽  
Ribosomal Protein L5

Developmental expression and 5S rRNA-binding activity of Xenopus laevis ribosomal protein L5

1989 ◽  
Vol 9 (12) ◽  
pp. 5281-5288
Author(s):  
W M Wormington
Keyword(s):  
Ribosomal Protein ◽  
Mammalian Cells ◽  
Ribosomal Proteins ◽  
5S Rrna ◽  
Yeast Cells ◽  
Developmental Expression ◽  
Rrna Synthesis ◽  
Ribosome Assembly ◽  
Subunit Assembly ◽  
Ribosomal Protein L5

Ribosomal protein L5 binds specifically to 5S rRNA to form a complex that is a precursor to 60S subunit assembly in vivo. Analyses in yeast cells, mammalian cells, and Xenopus embryos have shown that the accumulation of L5 is not coordinated with the expression of other ribosomal proteins. In this study, the primary structure and developmental expression of Xenopus ribosomal protein L5 were examined to determine the basis for its distinct regulation. These analyses showed that L5 expression could either coincide with 5S rRNA synthesis and ribosome assembly or be controlled independently of these events at different stages of Xenopus development. L5 synthesis during oogenesis was uncoupled from the accumulation of 5S rRNa but coincided with subunit assembly. In early embryos, the inefficient translation of L5 mRNA resulted in the accumulation of a stable L5-5S rRNA complex before ribosome assembly at later stages of development. Additional results demonstrated that L5 protein synthesized in vitro bound specifically to 5S rRNA.

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