Yasuko Matsumura

Tokai University, Hiratuka, Kanagawa, Japan

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Publications (8)35.75 Total impact

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    Makoto Senoo · Yasuko Matsumura · Sonoko Habu
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    ABSTRACT: Tumor suppressor p53 has been shown to repress expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a key mediator of tumor angiogenesis. The p63 gene, recently identified as a p53-relative, encodes multiple isoforms with structural and functional similarities and differences from p53. In this study, we show the evidence that the two major isoforms of the p63 gene, TAp63gamma (p51A) and dNp63alpha (p73L), represses and upregulates VEGF expression, respectively, on transcription and protein levels. Transient transfection assays show that a hypoxia-inducible factor (HIF) 1 binding site within the VEGF promoter region is responsible for both upregulation and repression by dNp63alpha and by TAp63gamma, respectively, of the VEGF promoter activity. We also show that TAp63gamma targets HIF1alpha for promoting proteasomal degradation but that dNp63alpha targets HIF1alpha for stabilization. Mammalian two-hybrid assays show that HIF1alpha-dependent transcription is repressed by TAp63gamma as well as by p53, whereas it is upregulated by dNp63alpha in collaboration with a transcription coactivator p300. Our data also show that dNp63alpha acts as a dominant-negative reagent toward both p53- and TAp63gamma-mediated degradation of HIF1alpha and repression of HIF1alpha-dependent transcription. These results suggest that p63 is involved in the regulation of the VEGF gene expression and that modulation of VEGF expression by TAp63gamma and dNp63alpha is closely correlated with their distinct roles on the regulation of HIF1alpha stability.
    Full-text · Article · May 2002 · Oncogene
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    ABSTRACT: A novel cDNA-encoding polypeptide of 545 amino acid residues was identified from a mouse testis cDNA library. The transcript of this gene, p59(scr), was predominantly expressed in the testis and was developmentally regulated during spermatogenesis. The encoded protein was expressed in spermatocytes and round spermatids within seminiferous tubules of the adult testis. Using an adult-mouse model of experimental unilateral cryptorchidism, it was observed that the expression of the p59(scr) mRNA was reduced in the cryptorchid testes in association with destruction of spermatogenesis. In vitro heat stress experiment further demonstrated that p59(scr) mRNA was more sensitive to heat stress than the other mRNA species, such as germ-cell-specific meiosis-activating kinase (mak) gene and a housekeeping beta-actin gene. Our results suggest that this novel p59(scr) gene is involved in spermatogenesis and may play an important role in development of testicular germ cells.
    Full-text · Article · May 2002 · Biochemical and Biophysical Research Communications
  • Source
    M Senoo · Y Matsumura · S Habu
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    ABSTRACT: Tumor suppressor p53 has been shown to repress expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a key mediator of tumor angiogenesis. The p63 gene, recently identified as a p53-relative, encodes multiple isoforms with structural and functional similarities and differences from p53. In this study, we show the evidence that the two major isoforms of the p63 gene, TAp63gamma (p51A) and dNp63alpha (p73L), represses and upregulates VEGF expression, respectively, on transcription and protein levels. Transient transfection assays show that a hypoxia-inducible factor (HIF) 1 binding site within the VEGF promoter region is responsible for both upregulation and repression by dNp63alpha and by TAp63gamma, respectively, of the VEGF promoter activity. We also show that TAp63gamma targets HIF1alpha for promoting proteasomal degradation but that dNp63alpha targets HIF1alpha for stabilization. Mammalian two-hybrid assays show that HIF1alpha-dependent transcription is repressed by TAp63gamma as well as by p53, whereas it is upregulated by dNp63alpha in collaboration with a transcription coactivator p300. Our data also show that dNp63alpha acts as a dominant-negative reagent toward both p53- and TAp63gamma-mediated degradation of HIF1alpha and repression of HIF1alpha-dependent transcription. These results suggest that p63 is involved in the regulation of the VEGF gene expression and that modulation of VEGF expression by TAp63gamma and dNp63alpha is closely correlated with their distinct roles on the regulation of HIF1alpha stability.
    Full-text · Article · Apr 2002 · Oncogene
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    ABSTRACT: We have generated mutant mice in which TCR beta chain enhancer (E(beta)) was replaced with the TCR alpha chain enhancer (E(alpha)). Using this mouse model, we analyzed (i) recombination status of the TCR beta chain genes after functional V(D)J rearrangements occurred in the first allele during double-negative (DN)-to-double-positive (DP) transition and (ii) involvement of E(beta) for the expression of rearranged TCR beta chain genes. Our data show that E(alpha) substituted for E(beta) function to express a similar extent of TCR beta chains exactly at the same time as did E(beta) (CD25+CD44- DN stage), although the proportion of TCR beta+ cells at this stage was low in mutant mice. At the DP stage, germline transcription and histone acetylation of D(beta)-J(beta) loci were detectable at a high degree in both mutant and wild-type mice. However, DP cells in mutant mice retained the germline D(beta)-J(beta) configuration at a higher frequency than that of wild-type mice, whereas both DP cells expressed TCR beta chains to a similar extent. These data suggest that chromatin opening has a limited impact on D(beta)-to-J(beta) recombination at the DP stage and that E(alpha) is functionally equivalent to E(beta) in promoting expression of functionally rearranged TCR beta chain genes through DN-to-DP transition.
    Full-text · Article · Dec 2001 · International Immunology
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    H Nishi · M Senoo · K H Nishi · B Murphy · T Rikiyama · Y Matsumura · S Habu · AC Johnson
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    ABSTRACT: Tumor suppressor p53 has been shown to transactivate epidermal growth factor receptor (EGFR) expression through binding to a putative p53 responsive element in the EGFR promoter between nucleotides -265 and -239 (EGFRp53RE). Isotypes of p63 gene products, recently identified as p53 relatives, have a similar function to transactivate several p53 target gene promoters. However, our results indicate that TAp63gamma has a very low ability to bind to the EGFRp53RE and surprisingly represses both basal EGFR promoter activity and endogenous EGFR expression. Transient transfection assays show that the EGFR promoter region between -348 and -293, containing two Sp1 sites, is crucial for the repression of the EGFR expression by TAp63gamma. Mutations in these Sp1 sites in the reporter constructs result in loss of the TAp63gamma repression effect. We further show that TAp63gamma directly interacts with Sp1 by immunoprecipitation analysis and that TAp63gamma impairs Sp1 binding to the target DNA site in electrophoretic mobility shift assays. These results suggest that TAp63gamma is involved in the regulation of the EGFR gene expression through interactions with basal transcription factors.
    Full-text · Article · Dec 2001 · Journal of Biological Chemistry
  • Source
    Makoto Senoo · Yasuko Matsumura · Sonoko Habu
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    ABSTRACT: The p51/p73L/p63/p40 gene, recently identified as a p53 homolog, encodes two major isoforms, p51A and p73L, which are suggested to have similar functions synonymous with p53 and dominant-negative activity toward both p53 and p51A, respectively. We have cloned a high affinity genomic fragment bound to p51A that was assigned to be a novel retrovirus long terminal repeat. Strikingly, this fragment was found to bind to both p53 and p73L with similar affinity to p51A. Additional demonstration with known p53 response elements suggested that DNA-binding profiles of p51A and p73L were very similar but were distinct from that of p53. Consistent with this novel finding, transient cotransfection experiments in mammalian cells suggested that p73L, when it was expressed at a low level, selectively suppressed p53-dependent transactivation of p21-luc and mdm2-luc but not of cyclinG-luc and bax-luc reporters. These data raise the possibility that p73L differentially modulates the p53 function according to the distinct DNA-binding affinity between these two proteins.
    Full-text · Article · Sep 2001 · Biochemical and Biophysical Research Communications
  • Source
    M Senoo · I Tsuchiya · Y Matsumura · T Mori · Y Saito · H Kato · T Okamoto · S Habu
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    ABSTRACT: We have recently identified a second p53 -related p73L gene, also referred to as p63 / p51 / p40 / KET gene, which encodes the 2 major isoforms p73L and p51 resulting from different exon usage at their amino terminal regions. Although p73L and p51 are suspected to play oncogenic and tumour suppressive roles in mammalian cells, respectively, no evidence of linkage between the expression of these isoforms and human cancers has been reported so far. In this study, we first investigated the expression profile of p51 and p73L in various human tumour cell lines and found that a novel isoform, termed DeltaNp73L, was predominantly expressed in squamous cell carcinomas. The expression profile of DeltaNp73L/p73L/p51 in primary human skin cancer specimens showed that the expression of p51 was frequently lost (62%) but was detected in all normal skin samples. In p51-expressing skin cancers, DeltaNp73L expression was associated at a high frequency (75%) though it was not detected in normal skin tissues. Transient co-transfection data indicate the possibility that DeltaNp73L can inhibit p53-, and more preferentially, p51-mediated transactivation. These data suggest that the loss of expression of p51 and/or the expression of DeltaNp73L might contribute to the pathogenesis of human squamous cell carcinomas.
    Full-text · Article · Jun 2001 · British Journal of Cancer
  • Source
    M. Senoo · Y. Matsumura · S. Habu
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    ABSTRACT: The p51/p73L/p63/p40 gene, recently identified as a p53 homolog, encodes two major isoforms, p51A and p73L, which are suggested to have similar functions synonymous with p53 and dominant-negative activity toward both p53 and p51A, respectively. We have cloned a high affinity genomic fragment bound to p51A that was assigned to be a novel retrovirus long terminal repeat. Strikingly, this fragment was found to bind to both p53 and p73L with similar affinity to p51A. Additional demonstration with known p53 response elements suggested that DNA-binding profiles of p51A and p73L were very similar but were distinct from that of p53. Consistent with this novel finding, transient cotransfection experiments in mammalian cells suggested that p73L, when it was expressed at a low level, selectively suppressed p53-dependent transactivation of p21-luc and mdm2-luc but not of cyclinG-luc and bax-luc reporters. These data raise the possibility that p73L differentially modulates the p53 function according to the distinct DNA-binding affinity between these two proteins.
    Full-text · Article · Jan 2001 · Biochemical and Biophysical Research Communications