Discovery of a p53 variant that controls metastasis

Abstract

The tumor suppressor p53 encoded by the tumor protein 53 (TP53) gene has been extensively studied since its discovery in 1979 (1, 2). The last four decades have seen the publication of an enormous number of reports on the role of p53 in suppressing cancer formation. These studies have demonstrated that TP53 mutations are the most common genetic alterations in human tumors (3).In PNAS, an article by Senturk et al. in the laboratory of R. Sordella describes the discovery of a new p53 isoform, named p53ψ, that may contribute to, rather than prevent, tumorigenesis (4). The new p53 isoform described by Senturk et al. derives from the use of an alternative 3′ splice acceptor site within TP53 intron 6. p53ψ encodes a protein of 27 kDa that lacks the critical residues necessary for p53 oligomerization, DNA binding, and nuclear localization. As a result, p53ψ does not have transcriptional activity, does not form oligomers, and is localized principally in the cytoplasm.Before the report of Senturk et al., 12 distinct p53 isoforms were known to exist in humans (5). Alternative splicing of TP53 intron 9 and use of the alternative promoter in intron 4 generates p53FL, p53β, p53γ, Δ133p53, Δ133p53β, and Δ133p53γ. Similarly, Δ40p53, Δ40p53β, and Δ40p53γ originate from the alternative splicing of TP53 intron 9 and the initiation of translation from a promoter in intron 2. Examination of mRNA levels of p53 variants has revealed that their generation is tissue specific, suggesting that internal promoter use and alternative splicing of TP53 are differentially regulated. Moreover, protein levels of p53 variants can be affected by external stimuli such as DNA damage induced by UV or ionizing radiation or changes in pH or oxygen concentration. With respect to function, p53 isoforms differ in their subcellular localization patterns and biological activities. Some p53 variants have been shown to interfere with the activity of p53 full length (FL) in vitro (6). In vivo, abnormal expression of p53 isoforms has been associated with disruption of the p53 FL response and, consequently, with accelerated aging, shorter life span, and promotion of tumor formation (7,8).The discovery of p53ψ raises the number of known p53 isoforms to 13. As is true for other p53 isoforms, this variant differs from p53 FL in its subcellular localization and putative function. However, unlike p53 isoforms that act as dominant-negative inhibitors of p53 FL activity, p53ψ does not interfere with p53 FL's mode of action. In fact, the authors show that the down-regulation of p53 FL's transcriptional targets in p53ψ-expressing cells is due solely to the generation of p53ψ transcripts at the expense of p53 FL mRNA.Senturk et al. initially discovered p53ψ as a variant expressed in a specific cell subset isolated from the lungs of mice that had been treated with naphthalene, which rapidly induces injury and necrosis in lung tissue. This cell subset was characterized by high expression of the glycoprotein CD44 and low expression of the heat stable antigen CD24 (CD44 hi CD...

The p53 tetramer shows an induced-fit interaction of the C-terminal domain with the DNA-binding domain

“… 57 , 58 , 59 , 60 , 61 , 62 , 63 The understanding of the highly complex signalling regulation of p53 64 , 65 , 66 , 67 , 68 , 69 , 70 has been further complicated by the presence of different protein isoforms. 71 , 72 , 73 , 74 P53 and its family members exert their actions by regulating the cellular microRNA in an intricate network. 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 Additionally, there is also a rather complex interaction between p53 and autophagy that acts in both directions.…”