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

Abstract

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.

Fig. 1

Nucleolar disruption. a Modes of nucleolar disruption and example treatments. b Characterization of nucleolar disruption: examples of clustering of images of treated nucleoli using morphology (top) and texture (Haralick) descriptors (bottom). Images shown in a and used for analysis in b are single confocal sections of immunofluorescence for fibrillarin, each image containing all nucleoli within a single nucleus

Fig. 2

Possible pathways of delivery of cell stress to p53. For a long time it has been considered that cell stresses directly activate p53 (dashed arrow), mainly through stress-induced kinases. The nucleolus model proposes that many of these stresses may stabilize p53 indirectly, by disrupting nucleoli (solid arrow). For most stresses, it is difficult to resolve which pathway predominates or whether the two pathways co-exist. Some stresses such as oxidative stress (see text) do not appear to affect nucleolar structure/function directly, but activate JNK, which in turn inhibits rDNA transcription (solid arrows). This pathway suggests stresses that normally would not affect nucleoli might be turned into nucleolar stresses by JNK, possibly to elicit the more general stress response that nucleoli support. JNK also phosphorylates p53 in response to stress (see text for further details and references)

Fig. 3

The nucleolar model of p53 regulation. Map of the proposed mechanisms for p53 homeostasis. The text boxes summarize the experimental observations that determine the sub-cellular localization and roles of the corresponding steps (numbers in circles)