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p53 and its isoforms in cancer

2014-10-12

p53 and its isoforms in cancer British Journal of Cancer 2007 Insem and Dundee UK paper q The p53 pathway is ubiquitously lost in human cancer either by p53 gene mutation (60% of cancers) or by lost of cell signalling upstream and downstream of p53 in the remaining cancers expressing WTp53 gene. q The recent discovery that p53 gene encodes for nine different p53 proteins (isoforms) may have a profound impact on our understanding of p53 tumour suppressor activity. q p53 is a transcription factor that binds directly and specifically as a tetramer to target sequences of DNA (p53-responsive elements (p53RE)) q However, the tumour suppressor p53 can trigger cell death independently of its transcriptional activity through subcellular translocation and activation of proapoptotic Bcl-2 family members q However, p53, p63 and p73 proteins are not entirely functionally redundant as each p53-family transgenic knockout mice develop distinct phenotypes, illustrating that p53, p63 and p73 have specific biological functions q p53 gene family members express multiple mRNA variants due to multiple splicing and alternative promoters. q p63 gene expresses at least six mRNA variants which encode for six different p63 protein isoforms (TAp63a, TAp63b, TAp63g, DNp63a, DNp63b and DNp63g q The p73 gene expresses at least seven alternatively spliced C-terminal isoforms (a, b, g, D, e, z, Z) and at least four alternatively spliced N-terminal isoforms, which contain different parts of the transactivation domain. HUMAN p53 ISOFORMS section q human p53 gene has indeed a dual gene structure similar to p73 and p63 genes q p53 gene transcription can be initiated in normal human tissue from two distinct sites upstream of exon1 and from an internal promoter located in intron 4 q the human p53 gene can encode at least nine different p53 protein isoforms q p53 transcriptional activity in responses to stresses such as ionising radiation, UV, pH and hypoxia q P53 isoforms have different subcellular localisations, suggesting that they can have distinct activities. q Interestingly, the dual gene structure of the p53 gene is conserved in human, Drosophila (Bourdon et al, 2005), mouse (Bourdon, unpublished data) and zebrafish (Chen et al, 2005), whereas the alternative splicing is species-specific q wild-type p53 activity may be modulated in the presence of p53 isoforms, and thus that regulation of p53 function in normal and tumour tissues in human is likely to be more complex than has been hitherto appreciated. q p53 can be involved in the regulation of so many biological functions (i.e. cell-cycle arrest, apoptosis, differentia- tion, replication, DNA repair, meiosis, mitosis, etc y ). q This strongly suggests that the differential expression of p53 isoforms could disrupt the p53 response and contribute to tumour formation nice diagram of human p53 gene structure q mutations of the p53 gene do not necessarily result in inactivation of p53 transcriptional activity q p53 isoforms have different subcellular localisations
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