Publications by authors named "Hirofumi Takada"

8 Publications

  • Page 1 of 1

Usefulness of one-point plasma SN-38G/SN-38 concentration ratios as a substitute for UGT1A1 genetic information after irinotecan administration.

Int J Clin Oncol 2014 Apr 19;19(2):397-402. Epub 2013 Apr 19.

Department of Pharmacy, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Kita-ku, Sakai, Osaka, 591-8025, Japan.

Background: It was recently reported that genetic polymorphisms of UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1), a glucuronidation enzyme, were associated with irinotecan (CPT-11) metabolism. The active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38) was glucuronidated (SN-38G) by UGT1A1. Genetic polymorphisms of UGT1A1 were associated with potentially serious adverse events, including neutropenia. Several studies have suggested that the dose of CPT-11 should be decreased in patients homozygous for UGT1A1*6 or UGT1A1*28, or double heterozygotes (*6/*28). However, the reference dose for patients with these genetic polymorphisms is unclear.

Methods: We investigated the relationship between the SN-38G/SN-38 concentration ratio and the dose of CPT-11 in 70 patients with colorectal cancer who received FOLFIRI-based regimens, by measuring the plasma concentrations of CPT-11, SN-38, and SN-38G.

Results: The SN-38G/SN-38 concentration ratio was lower in patients who were homozygous for UGT1A1*6, heterozygous for UGT1A1*6 or UGT1A1*28, or were double heterozygotes compared with patients with wild-type genes. The relative decreases in the SN-38G/SN-38 concentration ratio in patients homozygous for UGT1A1*6 and in double heterozygotes were greater than in patients heterozygous for UGT1A1*6 or UGT1A1*28. Interestingly, decreases in the SN-38G/SN-38 concentration ratio were associated with decreases in the neutrophil count and the final infusion dose of CPT-11.

Conclusion: Our results suggest that the SN-38G/SN-38 concentration ratio is an important factor for guiding dose adjustments, even in patients with wild-type genes. Therefore, the SN-38G/SN-38 concentration ratio, as an index of the patient's metabolic capacity, is useful for assessing dose adjustments of CPT-11.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10147-013-0558-1DOI Listing
April 2014

The internal loop of fission yeast Ndc80 binds Alp7/TACC-Alp14/TOG and ensures proper chromosome attachment.

Mol Biol Cell 2013 Apr 20;24(8):1122-33. Epub 2013 Feb 20.

Laboratory of Cell Regulation, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3LY, United Kingdom.

The Ndc80 outer kinetochore complex plays a critical role in kinetochore-microtubule attachment, yet our understanding of the mechanism by which this complex interacts with spindle microtubules for timely and accurate chromosome segregation remains limited. Here we address this issue using an ndc80 mutant (ndc80-NH12) from fission yeast that contains a point mutation within a ubiquitous internal loop. This mutant is normal for assembly of the Ndc80 complex and bipolar spindle formation yet defective in proper end-on attachment to the spindle microtubule, with chromosome alignment defects and missegregation happening later during mitosis. We find that ndc80-NH12 exhibits impaired localization of the microtubule-associated protein complex Alp7/transforming acidic coiled coil (TACC)-Alp14/tumor-overexpressed gene (TOG) to the mitotic kinetochore. Consistently, wild-type Ndc80 binds these two proteins, whereas the Ndc80-NH12 mutant protein displays a substantial reduction of interaction. Crucially, forced targeting of Alp7-Alp14 to the outer kinetochore rescues ndc80-NH12-mutant phenotypes. The loop was previously shown to bind Dis1/TOG, by which it ensures initial chromosome capture during early mitosis. Strikingly, ndc80-NH12 is normal in Dis1 localization. Genetic results indicate that the loop recruits Dis1/TOG and Alp7/TACC-Alp14/TOG independently. Our work therefore establishes that the Ndc80 loop plays sequential roles in spindle-kinetochore attachment by connecting the Ndc80 complex to Dis1/TOG and Alp7/TACC-Alp14/TOG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1091/mbc.E12-11-0817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623634PMC
April 2013

Acremomannolipin A, the potential calcium signal modulator with a characteristic glycolipid structure from the filamentous fungus Acremonium strictum.

Bioorg Med Chem Lett 2012 Nov 31;22(21):6735-9. Epub 2012 Aug 31.

Laboratory of Molecular Pharmacogenomics, School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.

By the newly developed assay method, the glycolipid Acremomannolipin A (1) was isolated from a filamentous fungus Acremonium strictum as a potential calcium signal modulator. The structure of 1 elucidated on the basis of intensive spectroscopic analyses as well as its degradation studies is quite unique: the d-mannopyranose is connected to d-mannitol through a β-glycoside linkage; all the hydroxyls in the mannose are highly masked as peresters with aliphatic acids, and this moiety is made hydrophobic, whereas the mannitol part exhibits a highly hydrophilic property. The compound (1) showed the characteristic bioactivity property, enabling calcineurin deletion cells to grow in the presence of Cl(-), which would be caused by calcium signal modulating. The activity was so potent as to exert the effect at a concentration of 200 nM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2012.08.085DOI Listing
November 2012

[Cell surface protein Ecm33 is involved in negative feedback regulation of MAP kinase signalling and development of the in vivo real-time monitoring of MAP kinase signalling].

Authors:
Hirofumi Takada

Yakugaku Zasshi 2011 ;131(8):1195-200

Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Osaka, Japan.

The mitogen-activated protein kinase (MAPK) pathways are signal transduction mechanisms that regulate many cellular processes in eukaryotic organisms, from yeasts to mammals. Multiple MAPKs regulate eukaryotic gene expression in response to various extracellular stimuli through phosphorylation of transcription factors. We have been studying the Pmk1 MAPK, a homologue of the mammalian ERK/MAPK in fission yeast. The Pmk1 MAPK regulates cell integrity and cell morphology. We have previously demonstrated that Atf1, a transcription factor downstream of the stress-activated MAPK pathway, serves also as a target of the Pmk1 MAPK signaling in fission yeast. Here, we identified ecm33⁺ gene, encoding a glycosyl-phosphatidylinositol (GPI)-anchored cell surface protein as a transcriptional target of Pmk1 and Atf1. The gene expression of ecm33⁺ is regulated by two transcription factors Atf1 and Mbx1. We also developed an in vivo real-time monitoring system of Atf1 or Mbx1 transcriptional activity, which enables to monitor the activation of the Pmk1 MAPK pathway by various stimuli. Finally, we demonstrated that Ecm33 is involved in the negative regulation of the Pmk1 MAPK signaling through the control of Ca²⁺ homeostasis. The ecm33 deleted cells displayed Ca²⁺ sensitivity and increased phosphorylation levels of Pmk1 MAPK. In addition, the Ecm33 overproducing cells displayed phenotypes closely similar to those of the pmk1 knockout cell. Collectively, Ecm33 plays a role in the negative feedback regulation of Pmk1 cell integrity signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/yakushi.131.1195DOI Listing
February 2012

[Regulation of RNA-binding proteins by MAPK signaling].

Tanpakushitsu Kakusan Koso 2009 Dec;54(16 Suppl):2207-12

View Article and Find Full Text PDF

Download full-text PDF

Source
December 2009

The cell surface protein gene ecm33+ is a target of the two transcription factors Atf1 and Mbx1 and negatively regulates Pmk1 MAPK cell integrity signaling in fission yeast.

Mol Biol Cell 2010 Feb 23;21(4):674-85. Epub 2009 Dec 23.

Laboratory of Molecular Pharmacogenomics, Laboratory of Molecular and Cellular Biology, and Laboratory of Bioinformatics, School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, 577-8502, Japan.

The highly conserved fission yeast Pmk1 MAPK pathway plays a key role in cell integrity by regulating Atf1, which belongs to the ATF/cAMP-responsive element-binding (CREB) protein family. We identified and characterized ecm33(+), which encodes a glycosyl-phosphatidylinositol (GPI)-anchored cell surface protein as a transcriptional target of Pmk1 and Atf1. We demonstrated that the gene expression of Ecm33 is regulated by two transcription factors Atf1 and a MADS-box-type transcription factor Mbx1. We identified a putative ATF/CREB-binding site and an RLM1-binding site in the ecm33(+) promoter region and monitored the transcriptional activity of Atf1 or Mbx1 in living cells using a destabilized luciferase reporter gene fused to three tandem repeats of the CRE and six tandem repeats of the Rlm1-binding sequence, respectively. These reporter genes reflect the activation of the Pmk1 pathway by various stimuli, thereby enabling the real-time monitoring of the Pmk1 cell integrity pathway. Notably, the Deltaecm33 cells displayed hyperactivation of the Pmk1 signaling together with hypersensitivity to Ca(2+) and an abnormal morphology, which were almost abolished by simultaneous deletion of the components of the Rho2/Pck2/Pmk1 pathway. Our results suggest that Ecm33 is involved in the negative feedback regulation of Pmk1 cell integrity signaling and is linked to cellular Ca(2+) signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1091/mbc.e09-09-0810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820430PMC
February 2010

Role of the RNA-binding protein Nrd1 and Pmk1 mitogen-activated protein kinase in the regulation of myosin mRNA stability in fission yeast.

Mol Biol Cell 2009 May 11;20(9):2473-85. Epub 2009 Mar 11.

Laboratory of Molecular Pharmacogenomics, and Laboratory of Pharmaceutical Analytical Chemistry, School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka 577-8502, Japan.

Myosin II is an essential component of the actomyosin contractile ring and plays a crucial role in cytokinesis by generating the forces necessary for contraction of the actomyosin ring. Cdc4 is an essential myosin II light chain in fission yeast and is required for cytokinesis. In various eukaryotes, the phosphorylation of myosin is well documented as a primary means of activating myosin II, but little is known about the regulatory mechanisms of Cdc4. Here, we isolated Nrd1, an RNA-binding protein with RNA-recognition motifs, as a multicopy suppressor of cdc4 mutants. Notably, we demonstrated that Nrd1 binds and stabilizes Cdc4 mRNA, thereby suppressing the cytokinesis defects of the cdc4 mutants. Importantly, Pmk1 mitogen-activated protein kinase (MAPK) directly phosphorylates Nrd1, thereby negatively regulating the binding activity of Nrd1 to Cdc4 mRNA. Consistently, the inactivation of Pmk1 MAPK signaling, as well as Nrd1 overexpression, stabilized the Cdc4 mRNA level, thereby suppressing the cytokinesis defects associated with the cdc4 mutants. In addition, we demonstrated the cell cycle-dependent regulation of Pmk1/Nrd1 signaling. Together, our results indicate that Nrd1 plays a role in the regulation of Cdc4 mRNA stability; moreover, our study is the first to demonstrate the posttranscriptional regulation of myosin expression by MAPK signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1091/mbc.e08-09-0893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675626PMC
May 2009

Atf1 is a target of the mitogen-activated protein kinase Pmk1 and regulates cell integrity in fission yeast.

Mol Biol Cell 2007 Dec 19;18(12):4794-802. Epub 2007 Sep 19.

Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, 577-8502, Japan.

In fission yeast, knockout of the calcineurin gene resulted in hypersensitivity to Cl(-), and the overexpression of pmp1(+) encoding a dual-specificity phosphatase for Pmk1 mitogen-activated protein kinase (MAPK) or the knockout of the components of the Pmk1 pathway complemented the Cl(-) hypersensitivity of calcineurin deletion. Here, we showed that the overexpression of ptc1(+) and ptc3(+), both encoding type 2C protein phosphatase (PP2C), previously known to inactivate the Wis1-Spc1-Atf1 stress-activated MAPK signaling pathway, suppressed the Cl(-) hypersensitivity of calcineurin deletion. We also demonstrated that the mRNA levels of these two PP2Cs and pyp2(+), another negative regulator of Spc1, are dependent on Pmk1. Notably, the deletion of Atf1, but not that of Spc1, displayed hypersensitivity to the cell wall-damaging agents and also suppressed the Cl(-) hypersensitivity of calcineurin deletion, both of which are characteristic phenotypes shared by the mutation of the components of the Pmk1 MAPK pathway. Moreover, micafungin treatment induced Pmk1 hyperactivation that resulted in Atf1 hyperphosphorylation. Together, our results suggest that PP2C is involved in a negative feedback loop of the Pmk1 signaling, and results also demonstrate that Atf1 is a key component of the cell integrity signaling downstream of Pmk1 MAPK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1091/mbc.e07-03-0282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2096581PMC
December 2007
-->