P53RDL1 regulates p53-dependent apoptosis

Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Nature Cell Biology (Impact Factor: 19.68). 04/2003; 5(3):216-23. DOI: 10.1038/ncb943
Source: PubMed


Although a number of targets for p53 have been reported, the mechanism of p53-dependent apoptosis still remains to be elucidated. Here we report a new p53 target-gene, designated p53RDL1 (p53-regulated receptor for death and life; also termed UNC5B). The p53RDL1 gene product contains a cytoplasmic carboxy-terminal death domain that is highly homologous to rat Unc5H2, a dependence receptor involved in the regulation of apoptosis, as well as in axon guidance and migration of neural cells. We found that p53RDL1 mediated p53-dependent apoptosis. Conversely, when p53RDL1 interacted with its ligand, Netrin-1, p53-dependent apoptosis was blocked. Therefore, p53RDL1 seems to be a previously un-recognized target of p53 that may define a new pathway for p53-dependent apoptosis. We suggest that p53 might regulate the survival of damaged cells by balancing the regulation of Netrin-p53RDL1 signalling, and cell death through cleavage of p53RDL1 for apoptosis.

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Available from: Koichi Matsuda, Jun 11, 2014
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    • "We have mainly applied the expression profile analysis after the exogenous introduction of wildtype p53 into cancer cells using the adenovirus vector system and identified more than 50 p53 downstream candidate genes [4]. Among them, we have performed the functional analysis of more than a dozen of target genes including p53R2, p53AIP1, and p53RDL1 [5] [6] [7] [8]. Here, we report the characterization of the Late Cornified Envelope Group I (LCE1) as a novel downstream target of p53. "
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    ABSTRACT: p53 is one of the most important tumor suppressor genes involved in human carcinogenesis. Although downstream targets of p53 and their biologic functions in cancer cells have been extensively investigated, it is still far from the full understanding. Here, we demonstrate that Late Cornified Envelope Group I (LCE1) genes, which are located in the LCE gene clusters encoding multiple well-conserved stratum-corneum proteins, are novel downstream targets of p53. Exogenous p53 overexpression using an adenoviral vector system significantly enhanced the expression of LCE1 cluster genes. We also observed induction of LCE1 expressions by DNA damage, which was caused by treatment with adriamycin or UV irradiation in a wild-type p53-dependent manner. Concordantly, the induction of LCE1 by DNA damage was significantly attenuated by the knockdown of p53. Among predicted p53-binding sites within the LCE1 gene cluster, we confirmed one site to be a p53-enhancer sequence by reporter assays. Furthermore, we identified LCE1 to interact with protein arginine methyltransferase 5 (PRMT5). Knockdown of LCE1 by specific small interfering RNAs significantly increased the symmetric dimethylation of histone H3 arginine 8, a substrate of PRMT5, and overexpression of LCE1F remarkably decreased its methylation level. Our data suggest that LCE1 is a novel p53 downstream target that can be directly transactivated by p53 and is likely to have tumor suppressor functions through modulation of the PRMT5 activity.
    Neoplasia (New York, N.Y.) 08/2014; 16(8). DOI:10.1016/j.neo.2014.07.008 · 4.25 Impact Factor
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    • "empty vector; and iii) 125 ng of pGL3-promoter vector with either the p21 promoter region corresponding to p53-binding site (for positive control) (20), that with p53-binding site 1 of HSPB7, that with p53-binding site 2 of HSPB7, or pGL3-Promoter mock vector (for negative control) by using FuGENE 6 transfection reagent (Roche). After 36-h incubation, luciferase activity was measured using the Dual Luciferase Assay System (Promega) (21). "
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    ABSTRACT: In order to identify genes involved in renal carcinogenesis, we analyzed the expression profile of renal cell carcinomas (RCCs) using microarrays consisting of 27,648 cDNA or ESTs, and found a small heat shock protein, HSPB7, to be significantly and commonly downregulated in RCC. Subsequent quantitative PCR (qPCR) and immunohistochemical (IHC) analyses confirmed the downregulation of HSPB7 in RCC tissues and cancer cell lines in both transcriptional and protein levels. Bisulfite sequencing of a genomic region of HSPB7 detected DNA hypermethylation of some segments of HSPB7 in RCC cells and concordantly 5-aza-2'-deoxycytidine (5-Aza-dC) treatment of cancer cells restored HSPB7 expression significantly. Ectopic introduction of HSPB7 in five RCC cell lines remarkably suppressed cancer cell growth. Interestingly, we found that HSPB7 expression could be induced by p53 in a dose-dependent manner, indicating that this gene functions in the p53 pathway. Our results imply that HSBP7 is likely to be a tumor suppressor gene regulated by p53 and its downregulation by hypermethylation may play a critical role in renal carcinogenesis.
    International Journal of Oncology 02/2014; 44(5). DOI:10.3892/ijo.2014.2314 · 3.03 Impact Factor
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    • "Netrin‐1, a soluble protein initially discovered as an axon navigation cue (Serafini et al, 1994), was recently proposed to play a crucial role in cancer progression by regulating apoptosis (Mazelin et al, 2004; Mehlen et al, 2011). Indeed, netrin‐1 receptors DCC and UNC5H,—i.e., UNC5H1, UNC5H2, UNC5H3 and UNC5H4 also called UNC5A, UNC5B, UNC5C or UNC5D— belong to the so‐called dependence receptor family (Llambi et al, 2001; Mehlen et al, 1998; Tanikawa et al, 2003). These dependence receptors, because of their ability to induce cell death when disengaged from their ligands, create cellular states of dependence on their respective ligands (Bredesen et al, 2005) and, consequently, may behave as tumour suppressors as they eliminate tumour cells that would develop in settings of ligand unavailability (Mazelin et al, 2004; Mehlen & Puisieux, 2006). "
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    ABSTRACT: The secreted factor netrin-1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin-1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin-1/receptors interaction interference are under preclinical evaluation. We show here that Doxorubicin, 5-Fluorouracil, Paclitaxel and Cisplatin treatments trigger, in various human cancer cell lines, an increase of netrin-1 expression which is accompanied by netrin-1 receptors increase. This netrin-1 upregulation which appears to be p53-dependent is a survival mechanism as netrin-1 silencing by siRNA is associated with a potentiation of cancer cell death upon Doxorubicin treatment. We show that candidate drugs interfering with netrin-1/netrin-1 receptors interactions potentiate Doxorubicin, Cisplatin or 5-Fluorouracil-induced cancer cell death in vitro. Moreover, in a model of xenografted nude mice, we show that systemic Doxorubicin treatment triggers netrin-1 upregulation in the tumour but not in normal organs, enhancing and prolonging tumour growth inhibiting effect of a netrin-1 interfering drug. Together these data suggest that combining conventional chemotherapies with netrin-1 interference could be a promising therapeutic approach.
    EMBO Molecular Medicine 12/2013; 5(12):1821-34. DOI:10.1002/emmm.201302654 · 8.67 Impact Factor
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