Abstract
The nucleolus has emerged as a cellular stress sensor and key regulator of p53-dependent and -independent stress responses. A variety of abnormal metabolic conditions, cytotoxic compounds, and physical insults induce alterations in nucleolar structure and function, a situation known as nucleolar or ribosomal stress. Ribosomal proteins, including RPL11 and RPL5, become increasingly bound to the p53 regulatory protein MDM2 following nucleolar stress. Ribosomal protein binding to MDM2 blocks its E3 ligase function leading to stabilization and activation of p53. In this review we focus on a number of novel regulators of the RPL5/RPL11-MDM2-p53 complex including PICT1 (GLTSCR2), MYBBP1A, PML and NEDD8. p53-independent pathways mediating the nucleolar stress response are also emerging and in particular the negative control that RPL11 exerts on Myc oncoprotein is of importance, given the role of Myc as a master regulator of ribosome biogenesis. We also briefly discuss the potential of chemotherapeutic drugs that specifically target RNA polymerase I to induce nucleolar stress.
Highlights
Nucleoli are dynamic structures described a few hundred years ago as distinct nuclear compartments, visualized under the light microscope, and the place of birth for ribosomes [1]
The various ribosomal RNA (rRNA) species are post-transcriptionally modified through interaction with small nucleolar ribonucleoproteins and additional processing factors in the dense fibrillar component (DFC) and granular component (GC) regions
The role of p53 in mediating the Diamond-Blackfan anemia (DBA) phenotype is not entirely clear, as studies in mammalian cancer cell lines show that RPL11 and RPL5 are required for p53 activation in response to nucleolar stress [51,78,81]
Summary
Nucleoli are dynamic structures described a few hundred years ago as distinct nuclear compartments, visualized under the light microscope, and the place of birth for ribosomes [1]. Several nucleolar proteins that are not considered to be involved in ribosome biogenesis were identified [10] It has become more and more evident over the last two decades that the nucleolus takes part in the regulation of multiple cellular functions, such as control of the cell-cycle apparatus, ageing, cellular stress responses, mRNA export and modification, protein degradation and sequestration. Many chemotherapeutic drugs inhibit either rDNA transcription or rRNA processing [28] but so far the contribution of these particular effects over the general DNA damage response/block of DNA replication in restraining overall cancer cell growth remains unclear. A majority of human cancers have lost wild type p53 functions, but recent results indicate that nucleolar stress results in cell cycle arrest independently of p53 function by other specific mechanisms, including degradation of the E2F-1 transcription factor [47]
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