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P53 Isoforms and Their Implications in Cancer

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P53 Isoforms and Their Implications in Cancer cancers Review p53 Isoforms and Their Implications in Cancer Maximilian Vieler and Suparna Sanyal * ID Department of Cell and Molecular Biology, Uppsala University, Box-596, BMC, Uppsala SE-75124, Sweden; [email protected] * Correspondence: [email protected] Received: 22 July 2018; Accepted: 18 August 2018; Published: 25 August 2018 Abstract: In this review we focus on the major isoforms of the tumor-suppressor protein p53, dysfunction of which often leads to cancer. Mutations of the TP53 gene, particularly in the DNA binding domain, have been regarded as the main cause for p53 inactivation. However, recent reports demonstrating abundance of p53 isoforms, especially the N-terminally truncated ones, in the cancerous tissues suggest their involvement in carcinogenesis. These isoforms are D40p53, D133p53, and D160p53 (the names indicate their respective N-terminal truncation). Due to the lack of structural and functional characterizations the modes of action of the p53 isoforms are still unclear. Owing to the deletions in the functional domains, these isoforms can either be defective in DNA binding or more susceptive to altered ‘responsive elements’ than p53. Furthermore, they may exert a ‘dominant negative effect’ or induce more aggressive cancer by the ‘gain of function’. One possible mechanism of p53 inactivation can be through tetramerization with the D133p53 and D160p53 isoforms—both lacking part of the DNA binding domain. A recent report and unpublished data from our laboratory also suggest that these isoforms may inactivate p53 by fast aggregation—possibly due to ectopic overexpression. We further discuss the evolutionary significance of the p53 isoforms. Keywords: p53; cancer; p53 isoform; D133p53; D160p53; D40p53; aggregation; prion 1. p53—The Gene, the Protein, and the Isoforms The tumor-suppressor protein p53 has been named the ‘guardian of the genome’ [1], as well as the ‘coordinator of the underlying processes of the hallmarks of cancer’ [2]. This is because its inactivation paves the way for cancers. p53 is a DNA binding protein which halts the cell cycle upon genomic stress [3] and essentially hinders proliferation of the cells with damaged DNA [4]. Upon DNA damage, p53-dimers bind to the p53-responsive elements (referred hereafter as RE), forming a dimer of dimers [5], initiating transcription of p53 responsive genes, and ultimately triggering the p53 pathway. The p53 pathway is involved in cell apoptosis, cell cycle arrest or DNA repair [3]. The main players of the p53 pathway are the mouse double minute protein 2 (MDM2) and the protein p14ARF. MDM2 is encoded by the MDM2 gene; it targets p53 for proteasomal degradation [6]. p14ARF is encoded by the ARF gene, which inhibits MDM2 and raises p53 levels [7]. Additionally, expression of p53 isoforms can alter the transcriptional targets of p53 [8,9]. p53 research is closely connected to clinical applications as an indicator for cancer types. The knowledge acquired from p53 research allows prediction of the possible outcomes of various cancers, and also aids in directing treatments by the use of specific compounds [10]. Since the early 1990s, the field of study of p53 has generated an ocean of information which is instrumental in understanding cancer. The next step is to discover the treatment of dysfunctional p53 itself. In order to do so, we need to understand the principles and the underlying mechanisms for formation of the p53 isoforms and their molecular interactions. Cancers 2018, 10, 288; doi:10.3390/cancers10090288 www.mdpi.com/journal/cancers Cancers 2018, 10, 288 2 of 19 Because it controls many cell-fate-deciding genes, p53 has a prominent role in cancer—both for the diagnosis and the treatment. Inactivation of p53 leads to malicious apoptosis. In simple words, the cells with DNA damage, whose normal fate is to die, can survive, divide irregularly, and cause cancer. There are many ways how p53 can be inactivated. Mutations in p53’s DNA binding domain (DBD) are the major cause of its inactivation. This makes the protein impaired to bind to the target DNA [11]. These mutations are widely studied and can be directly correlated with diseases. Other than the point mutations, various truncated forms of p53, commonly called as p53 isoforms, can also be responsible for its inactivation. The p53 isoforms are the main focus of this review and we discuss in detail their constitution, potential mechanisms of action, and the evolutionary significance for their creation. 1.1. The TP53 Gene and the Synthesis of the p53 Isoforms The TP53 gene is spread over 13 exons (Figure 1) located on the human chromosome 17p13.1 [12]. Using multiple promotors, alternative splicing, and the internal ribosome entry site (IRES), this gene can create 12 different isoforms of the p53 protein [13]. The isoform expression is regulated in Cancers 2018, 10, 288 2 of 19 the transcriptional level by alternative promoter usage and by alternative splicing of intron-2 and intron-9. DueBecause to the it controlspresence many of two cell-fate-deciding promotors, P1 genes,and P2, p53 TP53 has is a prominentoften referred role to in cancer—bothas a dual gene for [13]. the Thediagnosis duality and originates the treatment. from the Inactivation two promotors of p53 leadsP1 and to maliciousP2, leading apoptosis. to different In simple isoforms words, of p53. the cellsThe promotorwith DNA P1 damage, transcribes whose an mRNA normal piece fate iswhich to die, can can translate survive, either divide the full irregularly,-length p53 and (FLp53) cause cancer.or the ∆40p53There are isoform many waysstarting how with p53 codon can be 40. inactivated. In the latter Mutations case, the in p53’sFLp53 DNA transcript binding retains domain intron (DBD)-2 and are thethe major∆40p53 cause isoform of its synthesizes inactivation. from This an makes internal the ribosome protein impaired entry site to bind(IRES) to [14,15]. the target The DNA ∆40p53 [11]. isoformThese mutations can also be are formed widely from studied the and ∆40p53 can betranscript, directly correlatedwhich has with the diseases.intron-2 splicedOther than out fromthe point the p53mutations, transcript. various The truncated∆133 and forms∆160 isoforms of p53, commonly are transcribed called from as p53 the isoforms, promotor can P2, also starting be responsible with the methioninefor its inactivation. at codon The 133 p53 or 160, isoforms respectively. are the main focus of this review and we discuss in detail their constitution,Besides these, potential three mechanisms other isoforms of action, of p53 and show the evolutionaryvariations in significancethe C-terminus. for their These creation. isoforms, named α, β, and γ, are the results of alternative splicing of the exon 9 (Figure 1). The α isoform retains1.1. The all TP53 the Geneexons and including the Synthesis exons of the10 and p53 Isoforms11, which translate the hinge and the oligomerization domainThe ofTP53 p53.gene Alternative is spread oversplicing 13 exonsof the (Figure exon 19) locatedresults onin thethe humanexon 9β chromosome or the exon 17p13.1 9γ; these [ 12]. transcriptsUsing multiple afterpromotors, translation alternativelead to the splicing, β and γ andisoforms the internal of p53. ribosome In both cases, entry the site exons (IRES), have this genestop codons,can create which 12 different will lead isoforms to the termination of the p53 of protein translation, [13]. The causing isoform C-terminal expression truncation is regulated of varying in the lengthstranscriptional (Figure level1). by alternative promoter usage and by alternative splicing of intron-2 and intron-9. Figure 1 1.. ((TopTop) Canonical exons (boxes) and alternative 50′- untranslated region regionss ( (UTRs)UTRs) (checked boxes) of the TP53 gene. The The colored colored exons exons code code for for different different domains domains of of the the p53 p53 protein. protein. Promoter Promoter 1 1 produces aa transcripttranscript which which translates translates to to the the full-length full-length p53 p53 (FLp53) (FLp53) and and the Dthe40p53 ∆40p53 isoform; isoform; the latter the latteris translated is translated only ifonly intron-2 if intron is retained-2 is retained in the transcript.in the transcript. Promoter Promoter P2 produces P2 produces a transcript a transcript coding codingfor D133 for and ∆133D160p53 and ∆ isoforms160p53 isoforms starting startin from theg from 133th the and 133th 160th and codons. 160th Thecodons. C-terminal The C- isoformsterminal isoformsof p53 (α ,ofβ p53, and (αγ,) β are, and controlled γ) are controlled by alternative by alternative splicing ofsplicing the exon of 9.the ( Bottomexon 9.) ( DifferentBottom) Different domains domainsof the FLp53 of the and FLp53 their and correspondence their correspondence with the exonswith the (shown exons with (shown the samewith the color same code) color of thecode)TP53 of gene: transactivation domain I (TAD I); transactivation domain II (TAD II); proline rich domain (PRD); DNA-binding domain; hinge domain (HD) oligomerization domain (OD) C-terminal domain (CTD). The arrows indicate the start point (N-terminus) of the particular isoform and determine the domains included in the respective isoform. Bottom right: The open boxes represent the two other C-terminal isoform-variants β and γ. Due to the presence of two promotors, P1 and P2, TP53 is often referred to as a dual gene [13]. The duality originates from the two promotors P1 and P2, leading to different isoforms of p53. The promotor P1 transcribes an mRNA piece which can translate either the full-length p53 (FLp53) or the D40p53 isoform starting with codon 40. In the latter case, the FLp53 transcript retains intron-2 and the D40p53 isoform synthesizes from an internal ribosome entry site (IRES) [14,15]. The D40p53 isoform can also be formed from the D40p53 transcript, which has the intron-2 spliced out from the p53 transcript. The D133 and D160 isoforms are transcribed from the promotor P2, starting with the methionine at codon 133 or 160, respectively.
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