Publications

New modulators, effectors and functions of the p53 tumour supressor pathway

Apoptosis, and more recently senescence, have been identified as the two principal mechanisms by which p53 exerts its tumour suppressor capabilities. We and others have shown that the cellular responses to p53 expression can be modulated by a wide range of factors, including reactive oxygen species (ROS), the vitamin A (retinoic acid) pathway and pro-survival signals induced by p53 itself. Thus, identifying new pathways that contribute to p53 functions should help understand the antineoplastic mechanisms of p53.

Cellular responses to p53 activation

p53 is a critical regulator of the cell cycle and functions as a 'guardian of the genome'. The majority of human tumours show loss of p53 function, which underscores its importance in tumour suppression. As a transcription factor, p53 targets the expression of a variety of genes involved in specific cell fate decisions. In response to cellular stress induced by DNA damage, hypoxia or oncogenes, levels of p53 protein rise and trigger cell cycle arrest, senescence or apoptosis.

The factors determining these cell fate decisions are not well understood. Oncogenes such as ras or raf, as well as other stimuli, can induce a permanent arrest in normal fibroblasts in culture, a process that has been termed 'premature senescence' or STASIS ('stress or aberrant signalling-induced senescence'). Such arrest has morphological and functional characteristics similar to the replicative senescence phenotype observed in aging cells in culture after prolonged passages and telomere erosion.

Premature senescence is often mediated by CDK inhibitors p16 Ink4a and/or p21 Waf1, usually induced through the activation of tumour suppressors Rb and p53. The importance of senescence in tumour suppression was controversial until several studies showed that it prevents the emergence of transformed cells in vivo. It is still not clear what factors influence the upregulation and maintenance of the senescence pathway.

Role of ROS in p53 functions

ROS are a byproduct of normal oxidative processes related to cell metabolism. It has been proposed that ROS generation is an important component of the effects of certain antineoplastic therapies. However, because of their mutagenic and carcinogenic properties, increased levels of ROS are also believed to be involved in the initiation of several cancers. p53 activation has been shown to increase ROS.

Apoptosis triggered by p53 has been reported to be at least partly dependent on an increase of ROS. Also, both p21- and p53-induced senescence of cancer cells require elevated ROS levels to maintain the permanence of this arrest. Thus, ROS generation is an important mediator of p53 functions, and cell fate decisions after p53 upregulation can be influenced by ROS levels.

Indeed, we showed that the magnitude of p53 protein expression and subsequent ROS accumulation correlates with the induction of either arrest or apoptosis, and that altering the levels of intracellular ROS can modulate these responses.

The retinoic acid pathway in cancer

Vitamin A is a liposoluble factor necessary for most life forms, which animals cannot synthesise. Active retinoid metabolites are synthesised in target cells from the forms of vitamin A present in plasma. The active retinoic acids play important roles in embryonic development and organogenesis, as well as in maintenance of epithelia and the physiological functions of the immune system, the brain, the eye and the reproductive system.

Retinoids are known teratogens, but they also inhibit tumour cell growth. Of special interest is the effect of ATRA on acute promyelocytic leukemia, acting against the PML-RAR, a fusion protein responsible for the disease. Although RA have been successfully used against certain types of tumours, their mechanisms of action in cancer are not yet fully understood.

Modulators and effectors of p53

We study the p53 pathway at several levels (Figure 1). We are characterising novel p53 target genes that will help us to better understand the cellular effects of p53. This is leading to the identification of new p53 functions beyond its classic antineoplastic activity. For instance, we investigate the role of p53 in the defence against viral infection.

We also investigate how cell fate decisions after p53 activation can be modulated, with special interest in the mechanisms involved in senescence. We are currently exploring how oxygen tension and reactive oxygen species can contribute or interfere with the p53 response. Of special interest is the crosstalk between the p53 and the retinoic acid pathway, which we have found may play an important role in p53 functions.

Our data should help understand how cellular tumour suppressors function and provide a basis to design improved antineoplastic therapies.

Figure 1