Wakana Ohya-Shimada

Osaka University, Suika, Ōsaka, Japan

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Publications (4)9.66 Total impact

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    ABSTRACT: Hepatocyte growth factor (HGF) is a key ligand that elicits G1/S progression of epithelial cells, including hepatocytes. Proline is also required for DNA synthesis that is induced by growth factors in primary culture of hepatocytes. However, it remains unknown how proline contributes to the G1/S progression of hepatocytes. The primary culture of rat hepatocytes using HGF plus proline can be a conceptual model for elucidating the molecular linkage of amino acids and growth factors during G1/S progression. Using this in vitro model, we provide evidence that not only induction of cyclin-D1 by HGF but also up-regulation of cyclin-E1 by proline is required for hepatocytes to enter the S-phase. Proline-enhanced cyclin-E1 induction, without changing its mRNA level, is associated with the activation of mammalian target of rapamycin (mTOR)-dependent pathways. Indeed, proline enhanced the ribosomal protein S6 phosphorylations (i.e., mTOR target), concomitantly with an increase in cyclin-E1. Inversely, mTOR-inhibitor, rapamycin suppressed the proline-mediated induction of cyclin-E1. As a result, DNA synthesis of hepatocytes, which was induced by HGF in the presence of proline, was largely abolished by mTOR-inhibitor treatment. Such a co-mitogenic effect of proline was also dependent on collagen synthesis: collagen synthesis inhibitors, such as cis-OH-proline, diminished the proline-induced cyclin-E1, and then the G1/S progression of hepatocytes was also suppressed. Overall, proline-mediated mTOR activation and collagen synthesis were found critical for HGF-induced DNA synthesis, partly via the sufficient accumulation of cyclin-E1. This is the first report to demonstrate the molecular bridge between amino acids and growth factors that drive mitogenic outcomes.
    Biochemical and Biophysical Research Communications 04/2013; · 2.28 Impact Factor
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    ABSTRACT: Hepatocyte growth factor (HGF) and its receptor, c-Met, play pivotal roles in the nervous system during development and in disease states. However, the physiological roles of HGF in the adult brain are not well understood. In the present study, to assess its role in learning and memory function, we used transgenic mice that overexpress HGF in a neuron-specific manner (HGF-Tg) to deliver HGF into the brain without injury. HGF-Tg mice displayed increased alternation rates in the Y-maze test compared with age-matched wild-type (WT) controls. In the Morris water maze (MWM) test, HGF-Tg mice took less time to find the platform on the first day, whereas the latency to escape to the hidden platform was decreased over training days compared with WT mice. A transfer test revealed that the incidence of arrival at the exact location of the platform was higher for HGF-Tg mice compared with WT mice. These results demonstrate that overexpression of HGF leads to an enhancement of both short- and long-term memory. Western blot analyses revealed that the levels of N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, but not NR1, were increased in the hippocampus of HGF-Tg mice compared with WT controls, suggesting that an upregulation of NR2A and NR2B could represent one mechanism by which HGF enhances learning and memory performance. These results demonstrate that modulation of learning and memory performance is an important physiological function of HGF that contributes to normal CNS plasticity, and we propose HGF as a novel regulator of higher brain functions.
    Journal of Neuroscience Research 04/2012; 90(9):1743-55. · 2.97 Impact Factor
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    ABSTRACT: Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder associated with cerebellar neurodegeneration caused by expansion of a CAG repeat in the ataxin-7 gene. Hepatocyte growth factor (HGF), a pleiotrophic growth factor, displays highly potent neurotrophic activities on cerebellar neurons. A mutant c-met/HGF receptor knockin mouse model has revealed a role for HGF in the postnatal development of the cerebellum. The present study was designed to elucidate the effect of HGF on cerebellar neurodegeneration in a knockin mouse model of SCA7 (SCA7-KI mouse). SCA7-KI mice were crossed with transgenic mice overexpressing HGF (HGF-Tg mice) to produce SCA7-KI/HGF-Tg mice that were used to examine the phenotypic differences following HGF overexpression. The Purkinje cellular degeneration is thought to occur via cell-autonomous and non-cell autonomous mechanisms mediated by a reduction of glutamate transporter levels in Bergmann glia. The Purkinje cellular degeneration and reduced expression of glutamate transporters in the cerebellum of SCA7-KI mice were largely attenuated in the SCA7-KI/HGF-Tg mice. Moreover, phenotypic impairments exhibited by SCA7-KI mice during rotarod tests were alleviated in SCA7-KI/HGF-Tg mice. The bifunctional nature of HGF on both Purkinje cells and Bergmann glia highlight the potential therapeutic utility of this molecule for the treatment of SCA7 and related disorders.
    Neuroscience Research 03/2012; 73(2):115-21. · 2.20 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive degeneration of motoneurons. We have demonstrated that hepatocyte growth factor (HGF) attenuates loss of both spinal and brainstem motoneurons of ALS model mice expressing mutated human SOD1(G93A) (G93A). This study was designed to assess disease-dependent regulatory mechanisms of c-Met/HGF receptor (c-Met) activation in the facial motoneurons of G93A mice. Using double transgenic mice expressing HGF and mutated SOD1(G93A) (G93A/HGF), we showed that phosphorylation of c-Met tyrosine residues at positions 1230, 1234 and 1235 (phospho-Tyr), and thereby its activation, was slightly evident in G93A and highly obvious in G93A/HGF mice (but absent in WT and HGF-Tg mice). Phosphorylation of the c-Met serine residue at position 985 (phospho-Ser), a residue involved in the negative regulation of its activation, was evident in WT and HGF-Tg mice. Protein phosphatase 2A (PP2A), which is capable of dephosphorylating c-Met phospho-serine, is upregulated in the facial motoneurons of G93A and G93A/HGF mice compared with WT and HGF-Tg mice. Thus, c-Met activation is reciprocally regulated by phosphorylation between c-Met serine and tyrosine residues through PP2A induction in the presence or absence of mutant SOD1 expression, and HGF functions more efficiently in ALS and ALS-related diseases.
    Neuroscience Research 08/2009; 65(2):194-200. · 2.20 Impact Factor