Nucleolar control of p53: a cellular Achilles’ heel and a target for cancer therapy

Nucleoli perform a crucial cell function, ribosome biogenesis, and of critical relevance to the subject of this review, they are also extremely sensitive to cellular stresses, which can cause loss of function and/or associated structural disruption. In recent years, we have learned that cells take a...

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Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS 2014-03, Vol.71 (5), p.771-791
Main Authors: Vlatković, Nikolina, Boyd, Mark T, Rubbi, Carlos P
Format: Article
Language:English
Subjects:
Biochemistry
Biodegradation
biogenesis
Biomedical and Life Sciences
Biomedicine
Cancer
Cell Biology
cell nucleolus
Cell Nucleolus - metabolism
Cell Nucleolus - physiology
cells
Cellular biology
Drug therapy
Gene Expression Regulation, Neoplastic - genetics
homeostasis
Life Sciences
ligases
Models, Biological
Neoplasms - metabolism
Neoplasms - physiopathology
Protein Stability
Protein Transport - physiology
Proteolysis
Proto-Oncogene Proteins c-mdm2 - metabolism
Review
ribosomes
Ribosomes - metabolism
Stress, Physiological - physiology
Tumor Suppressor Protein p53 - metabolism
ubiquitin-protein ligase
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Summary:Nucleoli perform a crucial cell function, ribosome biogenesis, and of critical relevance to the subject of this review, they are also extremely sensitive to cellular stresses, which can cause loss of function and/or associated structural disruption. In recent years, we have learned that cells take advantage of this stress sensitivity of nucleoli, using them as stress sensors. One major protein regulated by this role of nucleoli is the tumor suppressor p53, which is activated in response to diverse cellular injuries in order to exert its onco-protective effects. Here we discuss a model of nucleolar regulation of p53, which proposes that key steps in the promotion of p53 degradation by the ubiquitin ligase MDM2 occur in nucleoli, thus providing an explanation for the observed link between nucleolar disruption and p53 stability. We review current evidence for this compartmentalization in p53 homeostasis and highlight current limitations of the model. Interestingly, a number of current chemotherapeutic agents capable of inducing a p53 response are likely to do so by targeting nucleolar functions and these compounds may serve to inform further improved therapeutic targeting of nucleoli.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-013-1361-x