SPATA18, a Spermatogenesis-Associated Gene, Is a Novel Transcriptional Target of p53 and p63

Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Molecular and Cellular Biology (Impact Factor: 4.78). 02/2011; 31(8):1679-89. DOI: 10.1128/MCB.01072-10
Source: PubMed


The transcription factor p53 functions not only to suppress tumorigenesis but also to maintain normal development and homeostasis.
Although p53 was implicated in different aspects of fertility, including spermatogenesis and implantation, the mechanism underlying
p53 involvement in spermatogenesis is poorly resolved. In this study we describe the identification of a spermatogenesis-associated
gene, SPATA18, as a novel p53 transcriptional target and show that SPATA18 transcription is induced by p53 in a variety of cell types of both human and mouse origin. p53 binds a consensus DNA motif
that resides within the first intron of SPATA18. We describe the spatiotemporal expression patterns of SPATA18 in mouse seminiferous tubules and suggest that SPATA18 transcription is regulated in vivo by p53. We also demonstrate the induction of SPATA18 by p63 and suggest that p63 can compensate for the loss of p53 activity in vivo. Our data not only enrich the known collection of p53 targets but may also provide insights on spermatogenesis defects that
are associated with p53 deficiency.

Download full-text


Available from: Chamutal Bornstein,
34 Reads
    • "Kawase et al. (2009) recently reported, that PHLDA3 is a p53 target gene that has been implicated in apoptosis, but its defi nite role in radiation response remains still uncharacterized (Amundson et al. 2008). As recently published by Bornstein et al. (2011) SPATA18 is also a transcriptional target of p53. Ionizing radiation induces a large variety of DNA lesions, including single-and double-strand breaks, and base and sugar damage (Fei and El-Deiry 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: To overcome the limitations of existing biodosimetry methods, we examined dose- and time-dependent gene expression changes in human peripheral blood lymphocytes after exposure to low-, medium- and high-dose ionizing radiation and searched for genes suitable for predicting radiation doses in the low-dose range. Additionally, the experiments are intended to provide new insights into the biological effects of exposures to low-, medium- and high-dose radiation. Gene expression analysis using whole human genome DNA microarrays was performed in human blood from six healthy donors irradiated ex vivo with 0, 0.02, 0.1, 0.5, 1, 2 and 4 Gy (γ rays, (137)Cs) at 6, 24 and 48 h after high-dose exposure (0.5-4 Gy), and at 24 and 48 h after low-dose exposures of 0.02 or 0.1 Gy. DNA microarray-based alterations in gene expression were found in a wide dose range in vitro and allowed us to identify nine genes with which low radiation doses could be accurately predicted with a sensitivity of 95.6%. In the low-, medium- and high-dose range, expression alterations increased with increasing dose and time after exposure, and were assigned to different biological processes such as nucleosome assembly, apoptosis and DNA repair response. We conclude from our results that gene expression profiles are suitable for predicting low-dose radiation exposure in a rapid and reliable manner and that acute low-dose exposure, as low as 20 mGy, leads to well-defined physiological responses in human peripheral blood lymphocytes.
    Radiation Research 09/2012; 178(4):304-12. DOI:10.2307/41679876 · 2.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Successful pregnancy requires a functionally normal blastocyst encountering a receptive maternal endometrium. Interestingly, the cell cycle regulator and tumor suppressor p53 has been reported to support reproduction in mice by regulating the expression of the leukemia inhibitory factor gene in the maternal endometrium. However, in humans the hormonal system orchestrating successful pregnancy is considerably different from rodents. Particularly, the primate-specific dimeric glycoprotein hormone human chorionic gonadotropin (hCG) is essential for blastocyst implantation and maintenance of early human pregnancy. Here we provide evidence that p53 selectively induces expression of the hCGbeta7 (CGB7) gene. None of the other CGB genes was found to be regulated by p53. We show that expression of the CGB7 gene is upregulated upon p53 induction in human HFF, HCT116 and DLD1 cells as well as in cell preparations enriched in human primary first-trimester trophoblasts. The increase in CGB7 levels upon doxorubicin treatment is lost after siRNA-directed knockdown of p53. Furthermore, we describe CGB7 as a direct transcriptional target gene of p53 by identifying a p53-responsive element in the CGB7 promoter using reporter assays, electrophoretic mobility shift assays and chromatin immunoprecipitations. With these results we provide a new link between p53 transcriptional activity and human reproduction.
    Cell cycle (Georgetown, Tex.) 11/2011; 10(21):3758-67. DOI:10.4161/cc.10.21.17946 · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We report here genome-wide analysis of the tumor suppressor p53 binding sites in normal human cells. 743 high-confidence ChIP-seq peaks representing putative genomic binding sites were identified in normal IMR90 fibroblasts using a reference chromatin sample. More than 40% were located within 2 kb of a transcription start site (TSS), a distribution similar to that documented for individually studied, functional p53 binding sites and, to date, not observed by previous p53 genome-wide studies. Nearly half of the high-confidence binding sites in the IMR90 cells reside in CpG islands, in marked contrast to sites reported in cancer-derived cells. The distinct genomic features of the IMR90 binding sites do not reflect a distinct preference for specific sequences, since the de novo developed p53 motif based on our study is similar to those reported by genome-wide studies of cancer cells. More likely, the different chromatin landscape in normal, compared with cancer-derived cells, influences p53 binding via modulating availability of the sites. We compared the IMR90 ChIPseq peaks to the recently published IMR90 methylome and demonstrated that they are enriched at hypomethylated DNA. Our study represents the first genome-wide, de novo mapping of p53 binding sites in normal human cells and reveals that p53 binding sites reside in distinct genomic landscapes in normal and cancer-derived human cells.
    Cell cycle (Georgetown, Tex.) 12/2011; 10(24):4237-49. DOI:10.4161/cc.10.24.18383 · 4.57 Impact Factor
Show more