Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain

Roth, Judith; Koch, Philipp; Contente, Ana; Dobbelstein, Matthias

doi:10.1038/sj.onc.1203500

Cited by 31 publications

(11 citation statements)

References 40 publications

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“…14) are consistent with this region playing an important role in regulating p53 activity. Moreover, the phenotype described for p53 lacking the polyproline region is similar to that observed in tumor-derived p53 mutants (15).…”

supporting

confidence: 56%

A Role for the Polyproline Domain of p53 in Its Regulation by Mdm2

Berger¹,

Sionov²,

Levine³

et al. 2001

Journal of Biological Chemistry

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The p53 protein plays a key role in the cellular response to stress by inducing cell growth arrest or apoptosis. The polyproline region of p53 has been shown to be important for its growth suppression activity. p53 protein lacking the polyproline region has impaired apoptotic activity and altered specificity for certain apoptotic target genes. Here we describe the role of this region in the regulation of p53 by its inhibitor Mdm2. p53 lacking the polyproline region was identified to be more susceptible to inhibition by Mdm2. Furthermore, the absence of this region renders p53 more accessible to ubiquitination, nuclear export, and Mdm2-mediated degradation. This increased sensitivity to Mdm2 results from an enhanced affinity of Mdm2 toward p53 lacking the polyproline region. Our results provide a new explanation for the impaired growth suppression activity of p53 lacking this region. The polyproline region is proposed to be important in the modulation of the inhibitory effects of Mdm2 on p53 activities and stability.

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supporting

confidence: 56%

A Role for the Polyproline Domain of p53 in Its Regulation by Mdm2

Berger¹,

Sionov²,

Levine³

et al. 2001

Journal of Biological Chemistry

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“…Although p53⌬62-91 activates the p21 promoter and many other p53-responsive promoters, its ability to activate a transiently transfected PIG3 promoter (18) and the expression of endogenous PIG3, PIG6, and PIG11 turned out to be severely reduced (19). Some tumor-derived mutations within the DNA binding domain of p53 result in a phenotype resembling p53⌬62-91 (20). This correlation further supports the model (10) that PIGs are mediators of p53-induced apoptosis.…”

supporting

confidence: 69%

The p53-induced Gene-6 (Proline Oxidase) Mediates Apoptosis through a Calcineurin-dependent Pathway

Rivera

Maxwell

2005

Journal of Biological Chemistry

153

100

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Proline oxidase is a p53-induced redox gene that can generate reactive oxygen species (ROS) and mediate apoptosis in tumor cells. We report that proline oxidase is a downstream effector in p53-mediated activation of the calcium/calmodulin-dependent phosphatase calcineurin in lung, renal, colon, and ovarian carcinoma cells. The activation of calcineurin by p53 and proline oxidase was detected by activation of the nuclear factor of activated T cells (NFAT), an established indicator of activated calcineurin. Both proline oxidase-and p53-induced activation of NFAT were sensitive to the calcineurin inhibitors cyclosporin A and FK-506, to scavengers of ROS, and to inhibitors of calcium mobilization. A proline oxidase antisense vector suppressed the ability of p53 to up-regulate proline oxidase, activate calcineurin, and induce apoptosis. Moreover, two renal carcinoma-derived mutant p53 proteins were deficient in inducing proline oxidase expression and in activating calcineurin. Inhibitors of calcineurin and calcium mobilization abolished proline oxidase-mediated apoptosis and reduced p53-induced apoptosis. Treatment of colon and ovarian carcinoma cells with the anticancer genotoxic agent etoposide upregulated both p53 and proline oxidase, activated calcineurin, and induced apoptosis. The etoposide-mediated activation of calcineurin and induction of apoptosis was markedly suppressed by FK-506 calcineurin inhibitor. We propose that proline oxidase mediates apoptosis through the generation of proline-dependent ROS, which then mobilize calcium and activate calcineurin. The activation of calcineurin-regulated transcription factor pathways by proline oxidase might affect gene expression events important to p53 regulation of cell growth and apoptosis.

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“…Transfections were carried out using Lipofectamine 2000 (Life Technologies), followed by luciferase assays (Promega). Plasmids: Reporter plasmids containing the promoters of p21/CDKN1A (el-Deiry et al, 1993), cyclin G (Jayaraman et al, 1998), and PIG3 were obtained from A Levine, Carol Prives, and derived (Roth et al, 2000;Contente et al, 2002) from a construct obtained from B Vogelstein (Polyak et al, 1997), respectively. Mutant p21/CDKN1A promoter constructs were obtained by the Quikchange methodology (Stratagene), using the oligonucleotides CTG GCC ATC AGG AAC ATT AAT TAA CAT GTT GAG CTC (to mutate the À2300 site) and GAA GAA GAC TGG GTT AAT TAA GGC AGA GAT TTC C (to mutate the À1400 site), as well as their reverse complements.…”

Section: Resultsmentioning

confidence: 99%

ΔNp73 can modulate the expression of various genes in a p53-independent fashion

et al. 2003

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DNp73a is an isoform of the p53 homologue p73 that lacks an amino-terminal transactivation domain and antagonizes the induction of gene expression by p53. Here, we examined whether DNp73a might also modulate cellular transcription in the absence of p53. The expression of DNp73a in the p53À/À cell line H1299 reduced the mRNA levels of p21/CDKN1A, but did not affect other p53-responsive genes. Correspondingly, the p21/ CDKN1A promoter was downregulated by DNp73a in reporter assays, whereas other p53-responsive promoters were not inhibited. To identify additional genes that respond to DNp73a in the absence of p53, microarrays carrying 4600 cDNA clones were hybridized. The expression of 30 genes was found to be altered more than threefold by overexpressed DNp73a. For instance, DNp73a increased the expression of EGR1 and CDC6, whereas it decreased the mRNA levels of c-MYC, cyclin A2/CCNA2, NF-jB1, ODC1, and RET finger protein/ RFP. Semiquantitative reverse transcription-PCR confirmed these results and further revealed that the influence of DNp73a on the regulation of these genes differs from other p73 isoforms and p53. We conclude that the impact of DNp73a on gene expression is not limited to p53-responsive genes. Rather, DNp73a can regulate the expression of a variety of genes independently of p53.

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Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain

Cited by 31 publications

References 40 publications

A Role for the Polyproline Domain of p53 in Its Regulation by Mdm2

A Role for the Polyproline Domain of p53 in Its Regulation by Mdm2

The p53-induced Gene-6 (Proline Oxidase) Mediates Apoptosis through a Calcineurin-dependent Pathway

ΔNp73 can modulate the expression of various genes in a p53-independent fashion

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