p53, transcriptional repression and drug sensitivity

Deregulation of the cell cycle (cell division) has long been known to contribute to the induction of cancer. Similarly, disruption of protein synthesis (cell growth) has also been shown to lead to several pathological conditions including cancer. 1 The tumor suppressor p53 is pivotal in inducing cell cycle arrest in response to DNA damage, and it has recently been recognized that p53 also plays a role in linking cell division with cell growth by sensing nucleolar stress. 2 When there is stress to ribosome biogenesis, and thus protein synthesis , several ribosomal proteins (RPs) such as RPL11, RPL23 and RPL5 have been shown to interact with Mdm2 and inhibit its E3 ubiquitin ligase activity towards p53. This leads to p53 stabilization and activation and enables cells to stop cell cycle progression in the absence of functional ribosomal biogenesis conditions. 3 This places p53 as an important regulator of both the DNA damage and protein synthesis pathways and suggests the coupling of these two processes may be important to preventing oncogenesis. in a previous issue of Cell Cycle, Llanos and Serrano link the ribosomal stress and p53 pathways with the DNA damage response. These authors show that depletion of endog-enous L37 led to an increase in p53 protein levels as well as its downstream targets p21 and Mdm2. Silencing of L37 also induced a decrease in S-phase cells, suggesting activation of p53-mediated cell cycle arrest. The authors also showed that knockdown of L37 increased the level of Mdm2 and Mdm2/L11 complexes, suggesting that in L37-depleted cells, Mdm2 remains inactivated by L11 and that the ribo-somal stress pathway mediates activation of p53 by L37 knockdown. The mechanism linking L37 depletion and increased L11-Mdm2 binding, however, is unclear and will need to be investigated in future studies. A variety of DNA damage agents have previously been shown to impair ribosomal biogenesis 4 and induce p53 stabilization dependent on L11 and S7. 5 However, the impact of DNA damage on the levels of ribosomal proteins has not been widely studied. in this report, Llanos and Serrano showed that cisplatin, Uv light and doxorubicin decreased the level of ectopically expressed L37. These authors then investigated whether L37 could contribute to p53 activation in response to genotoxic stress. L11 normally helps to activate the p53 response by binding and inactivating Mdm2, and previous studies have shown that down-regulation of L11 abrogates the activation of the p53 …