p53 -Dependent and -Independent Nucleolar Stress Responses

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.

The Chromatin-Associated Phf12 Protein Maintains Nucleolar Integrity and Prevents Premature Cellular Senescence

“…The nucleolus is the site of rRNA synthesis and nascent ribosome assembly (19). Previous studies pointed to a link between nucleolar stress and cellular senescence (20,21), although the molecular bases for this link remain elusive. To confirm our observations that Pf1 deletion affects expression of the rRNA processing machinery, we analyzed by immunofluorescence the levels of fibrillarin, SENP3, and UBF, three integral components of the nucleolus that participate in rRNA processing.…”

“…Thus, senescence is often seen as a mechanism to prevent damaged or mutated cells from proliferating uncontrollably (39). Interestingly, senescent cells often present morphological changes in the nucleolus, showing a single, very prominent nucleolus instead of a few smaller ones (20,21). Our results indicate that Pf1 controls specific steps of ribosome biogenesis, such as splicing, covalent modifications, and maturation of the pre-rRNA transcripts, and that the changes observed in the nucleoli of Pf1 Ϫ/Ϫ MEFs are unlikely to be an unspecific, secondary consequence of the changes in the rate at which the Pf1 Ϫ/Ϫ cells proliferate.…”

The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway

“…Further steps into this direction are required, as only a few p53-independent pathways are identified. Given that many cancers lack functional p53, it is of great importance to shed light on this emerging field of p53-independent pathways (5).…”

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

“…Stress influences nucleolar activity by affecting its morphology and three-dimensional structure, which is accompanied by alterations in nucleolar protein distribution and composition (Boulon et al, 2010). Under unfavorable environmental conditions, the nucleolar p53-linked stress-sensing mechanism allows the cell to halt the energyconsuming process of ribosome biogenesis, thereby slowing cell growth and proliferation (Holmberg Olausson et al, 2012;Zhang and Lu, 2009). Importantly, the nucleolus often acts together with CBs, which function as hubs for proteins that are involved in RNA processing and mRNA splicing (Staneǩ and Neugebauer, 2006).…”