Question Bank of Biology Questions and Answers - 3
Cancer cells display a number of abnormal propertiesin order to maintain their unrestrained growth and proliferation(). Ribosome biogenesis andprotein synthesis are in this context critical cellular processesnecessary for sustained cancer cell growth. Historically, ribosomeswere considered to be relatively stable entities. However, with thediscoveries of mutations affecting ribosomal protein (RP) genes inthe Diamond-Blackfan anemia (DBA) syndrome it became evident thatmutant RPs may cause complex, variable, and viable phenotypes(). Of note, DBA and othersyndromes involving mutant ribosomal or nucleolar proteins areoften associated with an increased life time risk of cancer(). Recently, a number of studiesusing next generation sequencing technologies describe RP genemutations also in cancers without a previous known history of bonemarrow failure disorder. By applying whole-exome sequencing, RNAseq, or whole-genome sequencing, RP gene mutations have beendetected in the genome of cancer cells, including from endometrialcancer, T-cell acute lymphoblastic leukemia (T-ALL), chroniclymphocytic leukemia (CLL), colorectal carcinomas, and high gradegliomas (–). The mechanisms underlying cancerdevelopment in the setting of a ribosome biogenesis defect remainpoorly understood. In this review, the most recent studies aresummarized and possible mechanisms by which mutant ribosomalproteins are linked to cancer development are discussed.
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The best known response to ribosome biogeneticdefects involves the tumor suppressor p53 that induces cell cyclearrest, senescence, apoptosis, or differentiation (,).A number of mouse models confirm the involvement of p53 inmediating certain phenotypes. For example, deletion of only oneallele of is enough to impair ribosome biogenesis, butthe early embryonic lethality is due to activation of p53-dependentcell cycle arrest and apoptosis rather than to a generaldownregulation of protein synthesis (). Furthermore, mutations in and in mice result inp53-dependent pigmentation defects (abnormal melanocyteproliferation), reduced body size, and anemia (). Rpl22 deficient mice develop Tlymphopenia by blocking αβ-T cell development in a p53-dependentmanner (,). Supporting observations also camefrom studies on the 5q-syndrome. The haplo-insufficiency of RPS14has a critical role in the development of the anemia thatcharacterizes 5q- syndrome ().Bone marrow cells from a mouse model of 5q- syndrome shows elevatedlevel of p53 and intercross with micerescued the macrocytic anemia and dysplasia phenotypes of the 5q-mouse (). For a more exhaustivelist of the different mouse models having mutations in ribosomalprotein genes we refer the reader to an informative overview byTerzian and Box ().
Activation of checkpoints for quality control ofribosome biogenesis is contributing to the disease manifestationsamong the ribosomopathies (,).The hematopoietic phenotype in DBA patients is for example at leastpartially linked to the activation of p53 (). What is the mechanism sensingribosome dysfunction leading to p53 activation? It is nowestablished that two RPs, namely RPL11 (uL5) and RPL5 (uL18),control p53-dependent cell cycle arrest, senescence or apoptosis inresponse to impaired ribosome biogenesis (,,).Loss of RPL5 or RPL11 also impairs ribosome biogenesis and stallscell proliferation similar to other essential RPs (,),but in the case of RPL11 or RPL5 there is no distinct cell cyclearrest (). RPL11 and RPL5regulate p53 as key components of the 5S ribonucleo-proteinparticle (5S RNP), in which the 5S rRNA is essential as well(–). When ribosome biogenesis is blocked,the 5S RNP pre-ribosomal complex is re-directed from assembly into60S ribosomes to MDM2 E3 ligase inhibition (–) (). 5S RNP promotes cellular senescence in response tooncogenic or replicative stress, given that oncogenic stressaccelerates rRNA transcription while replication stress delays rRNAprocessing both causing imbalances in ribosome production () (). The 5S RNP complex also act as a sensor responsible forstimulating fatty acid oxidation in response to nutrient depletion(), and sets the level of p53activation by ARF (p14ARF, p19Arf), a protein induced by oncogenes(). The ARF and RP-MDM2interactions are distinct regulatory pathways and function innon-redundant manner to boost the p53 response to oncogenic c-Mycyet to some extent they rely on each other (). ARF is a joker in the game andthere are now a number of unresolved issues regarding thefunctional interplay between ARF and 5S RNP. 5S RNP (RPL11/RPL5/5SrRNA and MDM2) has now with these findings emerged as a criticalcoordinator of signaling pathways at the interface of cell growthand proliferation control. Intuitively, p53 would then beinfluenced by a number of other factors regulating 5S RNP (,).