研究員

奥田博史

Hiroshi Okuda

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がんの弱点を見つけ創薬へ

我々は血液のがんである白血病の発病の仕組みを解き明かすことを試みています。白血病の多くは遺伝子が傷つけられてできた“がん遺伝子”が細胞を狂わせて発症します。私は、特に乳児や小児に頻発する難治性白血病のがん遺伝子からできる異常タンパク質“MLLキメラ”の機能を丁寧に調べることで、その弱点を見つけたい。がんの弱点を見つけることができれば、その弱点を突く薬の開発が可能となる。がん研究にとって非常に難しいこのようなサクセスストーリーをどうにかして成し遂げたい。このような大きな目標に向かって研究をする研究者の一人であることが自分の存在意義であると考えています。

 

 

研究業績

1.       Okuda H, Stanojevic B, Kanai A, Kawamura T, Takahashi S, Matsui H, Takaori-Kondo A, Yokoyama A. Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia. J. Clin. Invest. 127, 1918-1931 (2017)

 

2.       Okuda H, Takahashi S, Takaori-Kondo A and Yokoyama A. TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion- dependent transcription. Cell Cycle 15, 2712-2722 (2016)

 

3.       MacLean JA 2nd, King ML, Okuda H and Hayashi K. WNT7A Regulation by miR-15b in Ovarian Cancer. PLOS One 11, e0156109 (2016)

 

4.       Okuda H, Kanai A, Ito S, Matsui H and Yokoyama A. AF4 utilizes the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription. Nature Commun. 6, 8869 (2015)

 

5.       King ML, Lindberg ME, Stodden GR, Okuda H, Ebers SD, Johnson A, Montag A, Lengyel E, MacLean II JA and Hayashi K. WNT7A/β-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer. Oncogene 34, 3452-3462 (2015)

 

6.       Okuda H, Kawaguchi M, Kanai A, Matsui H, Kawamura T, Inaba T, Kitabayashi I and Yokoyama A. MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters. Nucleic Acid Res. 42, 4241-4256 (2014)

 

7.       Xing F, Kobayashi A, Okuda H, Watabe M, Pai SK, Pandey PR, Hirota S, Wilber A, Mo YY, Moore BE, Liu W, Fukuda K, Iiizumi M, Sharma S, Liu Y, Wu K, Peralta E and Watabe K. Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain. EMBO Mol. Med. 5, 384-396 (2013)

 

8.       Okuda H, Xing F, Pandey PR, Sharma S, Watabe M, Pai SK, Mo YY, Iiizumi-Gairani M, Hirota S, Liu Y, Wu K, Pochampally R and Watabe K. miR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4. Cancer Res. 73, 1434-1444 (2013)

 

9.       Yoshioka S, King ML, Ran S, Okuda H, MacLean JA 2nd, McAsey ME, Sugino N, Brard L, Watabe K and Hayashi K. WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway. Molecular Cancer Res. 10, 469-482 (2012)

 

10.    Liu W, Xing F, Iiizumi-Gairani M, Okuda H, Watabe M, Pai SK, Pandey PR, Hirota S, Kobayashi A, Mo YY, Fukuda K, Li Y and Watabe K. N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis. EMBO Mol. Med. 4, 93-108 (2012)

 

11.    Okuda H, Kobayashi A, Xia B, Watabe M, Pai SK, Hirota S, Xing F, Liu W, Pandey PR, Fukuda K, Modur V, Ghosh A, Wilber A and Watabe K. Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells. Cancer Res. 72, 537-547 (2012)

 

12.    Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, Wilber A and Watabe K. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp. Med. 208, 2641-2655 (2011)

 

13.    Pandey PR, Okuda H, Watabe M, Pai SK, Liu W, Kobayashi A, Xing F, Fukuda K, Hirota S, Sugai T, Wakabayashi G, Koeda K, Kashiwaba M, Suzuki K, Chiba T, Endo M, Fujioka T, Tanji S, Mo YY, Cao D, Wilber AC and Watabe K. Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase. Breast Cancer Res. Treat. 130, 387-398 (2011)

 

14.    Xing F, Okuda H, Watabe M, Kobayashi A, Pai SK, Liu W, Pandey PR, Fukuda K, Hirota S, Sugai T, Wakabayashi G, Koeda K, Kashiwaba M, Suzuki K, Chiba T, Endo M and Watabe K. Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30, 4075-4086 (2011)

 

15.    Liu W, Furuta E, Shindo K, Watabe M, Xing F, Pandey PR, Okuda H, Pai SK, Murphy LL, Cao D, Mo YY, Kobayashi A, Iiizumi M, Fukuda K, Xia B and Watabe K. Cacalol, a natural sesquiterpene, induces apoptosis in breast cancer cells by modulating Akt-SREBP-FAS signaling pathway. Breast Cancer Res. Treat. 128, 57-68 (2011)

 

16.    Liu W, Iiizumi-Gairani M, Okuda H, Kobayashi A, Watabe M, Pai SK, Pandey PR, Xing F, Fukuda K, Modur V, Hirota S, Suzuki K, Chiba T, Endo M, Sugai T and Watabe K. KAI1 is engaged in NDRG1 gene-mediated metastasis suppression through ATF3-NFkappaB complex in human prostate cancer. J. Biol. Chem. 286, 18949-18959 (2011)

 

17.    Furuta E, Okuda H, Kobayashi A and Watabe K. Metabolic genes in cancer: their roles in tumor progression and clinical implications. Biochim. Biophys. Acta. Rev. Cancer 1805, 141-152 (2010)

 

18.    Iiizumi M, Bandyopadhyay S, Pai SK, Watabe M, Hirota S, Hosobe S, Tsukada K, Miura K, Saito K, Furuta E, Liu W, Xing F, Okuda H, Kobayashi A and Watabe K. RhoC promotes metastasis via activation of the Pyk2 pathway in prostate cancer. Cancer Res. 68, 7613-7620 (2008)

 

19.    Okuda H, Sakuhana C, Yamamoto R, Mizukami Y, Kawai R, Sumita Y, Koga M, Shirai M and Matsuda K. The intermediate domain defines broad nucleotide selectivity for protein folding in Chlamydophila GroEL1. J. Biol. Chem. 283, 9300-9307 (2008)

 

20.    Okuda H, Sakuhana C, Yamamoto R, Kawai R, Mizukami Y and Matsuda K. Effects of divalent cations on encapsulation and release in the GroEL-assisted folding. Biometals 20, 903-910 (2007)

 

21.    Ihara M, Brown LA, Ishida C, Okuda H, Sattelle DB and Matsuda K. Actions of imidacloprid, clothianidin and related neonicotinoids on nicotinic acetylcholine receptors of American cockroach neurons and their relationships with insecticidal potency. J. Pestic. Sci. 31, 35-40 (2006)

 

22.    Ihara M, Ishida C, Okuda H, Ozoe Y and Matsuda K. Differential blocking actions of 4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) and gamma-hexachlorocyclohexane (gamma-HCH) on gamma-aminobutyric acid- and glutamate-induced responses of American cockroach neurons. Invert. Neurosci. 5, 157-164 (2005)

 

23.    Fukuoka K, Sawabe A, Sugimoto T, Koga M, Okuda H, Kitayama T, Shirai M, Komai K, Komemushi S and Matsuda K. Inhibitory actions of several natural products on proliferation of rat vascular smooth muscle cells by Hsp60 from Chlamydia pneumoniae J138. J. Agric. Food Chem. 52, 6326-6329 (2004)

 

24.    Shimomura M, Okuda H, Matsuda K, Komai K, Akamatsu M and Sattelle DB. Effects of mutations of a glutamine residue in loop D of the alpha 7 nicotinic acetylcholine receptor on agonist profiles for neonicotinoid insecticides and related ligands. Br. J. Pharmacol. 137, 162-169 (2002)