SHIMIZU Kouhei

写真a

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Title

Assistant Professor

Laboratory location

Abeno Campus

Research Areas 【 display / non-display

Chemical biology, Tumor biology, Molecular biology, Pathological medical chemistry, Immunology

Current Career 【 display / non-display

  • Osaka City University   Graduate School of Medicine   Basic Medicine Course   Assistant Professor  

 

Published Papers 【 display / non-display

  • Interplay between protein acetylation and ubiquitination controls MCL1 protein stability.

    Shimizu K, Gi M, Suzuki S, North BJ, Watahiki A, Fukumoto S, Asara JM, Tokunaga F, Wei W, Inuzuka H

    Cell reports  37 ( 6 ) 109988 - 109988 2021.11  [Refereed]

     View Summary

    The anti-apoptotic myeloid cell leukemia 1 (MCL1) protein belongs to the pro-survival BCL2 family and is frequently amplified or elevated in human cancers. MCL1 is highly unstable, with its stability being regulated by phosphorylation and ubiquitination. Here, we identify acetylation as another critical post-translational modification regulating MCL1 protein stability. We demonstrate that the lysine acetyltransferase p300 targets MCL1 at K40 for acetylation, which is counteracted by the deacetylase sirtuin 3 (SIRT3). Mechanistically, acetylation enhances MCL1 interaction with USP9X, resulting in deubiquitination and subsequent MCL1 stabilization. Therefore, ectopic expression of acetylation-mimetic MCL1 promotes apoptosis evasion of cancer cells, enhances colony formation potential, and facilitates xenografted tumor progression. We further demonstrate that elevated MCL1 acetylation sensitizes multiple cancer cells to pharmacological inhibition of USP9X. These findings reveal that acetylation of MCL1 is a critical post-translational modification enhancing its oncogenic function and provide a rationale for developing innovative therapeutic strategies for MCL1-dependent tumors.

    DOI PubMed

  • Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer.

    Dang F, Nie L, Zhou J, Shimizu K, Chu C, Wu Z, Fassl A, Ke S, Wang Y, Zhang J, Zhang T, Tu Z, Inuzuka H, Sicinski P, Bass AJ, Wei W

    Nature communications  12 ( 1 ) 5386 - 5386 2021.09  [Refereed]

     View Summary

    Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors.

    DOI PubMed

  • Th2 cell-derived histamine is involved in nasal Th2 infiltration in mice.

    Iwasaki N, Terawaki S, Shimizu K, Oikawa D, Sakamoto H, Sunami K, Tokunaga F

    Inflammation research : official journal of the European Histamine Research Society ... [et al.]  70 ( 5 ) 539 - 541 2021.05  [Refereed]

     View Summary

    OBJECTIVE: Histamine derived from mast cells and basophils plays important roles in inducing allergic symptoms. Although T cells also produce histamine, the involvement of the histamine produced from T cells has remained enigmatic. We sought to reveal the roles of T helper 2 (Th2) cell-derived histamine in nasal allergic disorders. METHODS: The histamine production from Th2 cells was measured by EIA. The mRNA expression of histidine decarboxylase (HDC) was measured by real-time PCR. To investigate the roles of Th2 cell-derived histamine in vivo, we analyzed an antigen-specific Th2 cell transfer mouse model. RESULTS: Th2 cells produced histamine by T cell receptor stimulation, and these properties were specific for Th2 cells, but not Th1 cells and naïve CD4 T cells. The histamine produced from Th2 cells was involved in the infiltrations of Th2 cells in response to antigen exposure. CONCLUSION: These results suggest that Th2 cell-derived histamine play important roles in nasal allergic disorders.

    DOI PubMed

  • Th2 cells and macrophages cooperatively induce allergic inflammation through histamine signaling.

    Iwasaki N, Terawaki S, Shimizu K, Oikawa D, Sakamoto H, Sunami K, Tokunaga F

    PloS one  16 ( 3 ) e0248158 2021  [Refereed]

    DOI PubMed

  • Phosphorylation-dependent osterix degradation negatively regulates osteoblast differentiation.

    Hoshikawa S, Shimizu K, Watahiki A, Chiba M, Saito K, Wei W, Fukumoto S, Inuzuka H

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology  34 ( 11 ) 14930 - 14945 2020.11  [Refereed]

    DOI PubMed

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Grant-in-Aid for Scientific Research 【 display / non-display

  • Establishment of a method for improving the efficiency of stem cell differentiation using a protein knockdown strategy

    Project/Area Number : 18K19282  Grant-in-Aid for Challenging Research (Exploratory) Representative

    Project Year :

    2018.06
    -
    2020.03
     

     View Summary

    The purpose of this study is to establish a novel method to improve the efficiency and reproducibility of stem cell differentiation. To this end, we employed a protein knockdown strategy based on small-molecule compounds-inducible proteasomal degradation for controlling cell differentiation. The method developed in this study would be helpful to identify the compounds and its degradation target which enables to regulate cell differentiation.

  • Molecular mechanisms of p75NTR modulation in the regeneration of pulp sensory function

    Project/Area Number : 18K19632  Grant-in-Aid for Challenging Research (Exploratory) Partaker / Other

    Project Year :

    2018.06
    -
    2020.03
     

     View Summary

    Efficient regeneration of pulp sensory function requires neural and axon regeneration and proper axon guidance in the dental pulp. In this study, we focused on the regulatory mechanisms of p75 neurotrophin receptor (p75NTR), an essential factor for neural differentiation, survival, and axon elongation. We found that post-translational modifications play a role in the regulation of p75NTR and modulate its activity. The findings of this study will provide an insight into developing a potential approach for the efficient regeneration of pulp function.

  • Identification of proteolytic signaling pathways regulating reprogramming during iPS cell generation

    Project/Area Number : 16K15811  Grant-in-Aid for challenging Exploratory Research Partaker / Other

    Project Year :

    2016.04
    -
    2018.03
     

    Partaker : SAWASAKI Tatsuya, SHIMIZU Kouhei

     View Summary

    Direct reprogramming of somatic cells to iPS cells involves global changes in epigenetic modification and gene expression. SKP2 E3 ligase is reported to play essential roles in epigenetic transcriptional regulation through degrading histone methyltransferases including MLL, PR-SET7, and CARM1. Here, to characterize the role of SKP2 signaling in human iPS generation, we conducted a screening of SKP2 interacting proteins and identified a RING-family protein as the E3 ligase of SKP2. Furthermore, we found that the protein levels of SKP2 and the RING E3 ligase are associated with the process of iPS generation. These data suggest that the identified E3 cascade may play important roles in epigenetic reprogramming of somatic to iPS cells.