Tomoo Iwakuma

University of Kansas, Lawrence, Kansas, United States

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Publications (35)297.28 Total impact

  • Ken Sasaki · Hiroshi Kurahara · S Natsugoe · Tomoo Iwakuma · Danny R. Welch ·

    Cancer Research 08/2015; 75(15 Supplement):3264-3264. DOI:10.1158/1538-7445.AM2015-3264 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):2338-2338. DOI:10.1158/1538-7445.AM2015-2338 · 9.33 Impact Factor
  • Hiromi Sasaki · Swathi V Iyer · Ken Sasaki · Ossama W Tawfik · Tomoo Iwakuma ·
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    ABSTRACT: Osteosarcoma, the most common type of primary bone cancer, is the second highest cause of cancer-related death in pediatric patients. To understand the mechanisms behind osteosarcoma progression and to discover novel therapeutic strategies for this disease, a reliable and appropriate mouse model is essential. For this purpose, osteosarcoma cells need to be injected into the bone marrow. Previously, the intratibial and intrafemoral injection methods were reported; however, the major drawback of these methods is the potential leakage of tumor cells from the injection site during or after these procedures. To overcome this, we have established an improved method to minimize leakage in an orthotopic mouse model of osteosarcoma. By taking advantage of the anatomical benefits of the femur with less bowing and larger medullary cavity than those of the tibia, osteosarcoma cells are injected directly into the femoral cavity following reaming of its intramedullary space. To prevent potential leakage of tumor cells during and after the surgery, the injection site is sealed with bone wax. This method requires a minor surgery of approximately 15 minutes under anesthesia. Our established orthotopic osteosarcoma model could serve as a valuable and reliable tool for examining tumor progression of various types of bone tumors. Copyright © 2015 Elsevier Inc. All rights reserved.
    Analytical Biochemistry 06/2015; 486. DOI:10.1016/j.ab.2015.06.030 · 2.22 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with increasing incidence. Despite curative surgical resection and advanced chemotherapy, its survival rate remains low. The presence of microvascular invasion and occult metastasis is one of the major causes for this poor outcome. MDM2 Binding Protein (MTBP) has been implicated in the suppression of cell migration and cancer metastasis. However, clinical significance of MTBP, particularly in human cancer, is poorly understood. Specifically, clinical relevance of MTBP in human HCC has never been investigated. Here we demonstrated that expression of MTBP was significantly reduced in human HCC tissues compared to adjacent non-tumor tissues. MTBP expression was negatively correlated with capsular/vascular invasion and lymph node metastasis. Overexpression of MTBP resulted in the suppression of the migratory and metastatic potential of HCC cells, while its downregulation increased the migration. Consistent with the previous report, MTBP endogenously bound to alpha-actinin 4 (ACTN4) and suppressed ACTN4-mediated cell migration in multiple HCC cell lines. However, MTBP also inhibited migratory potential of PLC/PRF/5 HCC cells whose migration was not altered by manipulation of ACTN4 expression. These results suggest that mechanisms behind MTBP-mediated migration suppression may not be limited to the pathway involving ACTN4 in certain cellular contexts. Additionally, as a potential mechanism for reduced MTBP expression in tumors, we found that MTBP expression was increased following the treatment with histone deacetylase inhibitors (HDIs). Our study, for the first time, provides clinical relevance of MTBP in the suppression of HCC metastasis.
    Clinical and Experimental Metastasis 03/2015; 32(4). DOI:10.1007/s10585-015-9706-5 · 3.49 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):5163-5163. DOI:10.1158/1538-7445.AM2014-5163 · 9.33 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):1990-1990. DOI:10.1158/1538-7445.AM2014-1990 · 9.33 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):135-135. DOI:10.1158/1538-7445.AM2014-135 · 9.33 Impact Factor
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    ABSTRACT: KISS1 is a broadly functional secreted proprotein that is then processed into small peptides, termed kisspeptins (KP). Since sequence analysis showed cleavage at KR or RR dibasic sites of the nascent protein, it was hypothesized that enzyme(s) belonging to the proprotein convertase family of proteases process KISS1 to generate KP. To this end, cell lines over-expressing KISS1 were treated with the proprotein convertase inhibitors, Dec-RVKR-CMK and α1-PDX, and KISS1 processing was completely inhibited. To identify the specific enzyme(s) responsible for KISS1 processing, mRNA expression was systematically analyzed for six proprotein convertases found in secretory pathways. Consistent expression of the three proteases - furin, PCSK5 and PCSK7 - were potentially implicated in KISS1 processing. However, shRNA-mediated knockdown of furin - but not PCSK5 or PCSK7 - blocked KISS1 processing. Thus, furin appears to be the essential enzyme for the generation of kisspeptins.
    PLoS ONE 01/2014; 9(1):e84958. DOI:10.1371/journal.pone.0084958 · 3.23 Impact Factor
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    ABSTRACT: Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the "Warburg Effect." Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerobic glycolysis decreases and oxidative phosphorylation predominates. However, when KISS1 is missing the secretion signal peptide (ΔSS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30-50% more mitochondrial mass than ΔSS-expressing cells, which is accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1α, a master co-activator that regulates mitochondrial mass and metabolism. PGC1α-mediated downstream pathways (i.e. fatty acid synthesis and β-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with NRF1, a major transcription factor involved in mitochondrial biogenesis. Since the downstream effects could be reversed using shRNA to KISS1 or PGC1α, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism and metastasis.
    Cancer Research 12/2013; 74(3). DOI:10.1158/0008-5472.CAN-13-1183 · 9.33 Impact Factor
  • Qian Bi · Rui Fan · Neeraj Agarwal · Swathi V. Iyer · Jie Ding · Tomoo Iwakuma ·

    Cancer Research 08/2013; 73(8 Supplement):3874-3874. DOI:10.1158/1538-7445.AM2013-3874 · 9.33 Impact Factor

  • Cancer Research 08/2013; 73(8 Supplement):3860-3860. DOI:10.1158/1538-7445.AM2013-3860 · 9.33 Impact Factor
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    Swathi V Iyer · Tomoo Iwakuma ·
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    ABSTRACT: Comment on: Xue Y, et al. Cell Cycle 2012; 11: In this issue.
    Cell cycle (Georgetown, Tex.) 10/2012; 11(22). DOI:10.4161/cc.22606 · 4.57 Impact Factor
  • Tomoo Iwakuma · Neeraj Agarwal ·
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    ABSTRACT: MDM2 binding protein (MTBP) is a protein that interacts with oncoprotein murine double minute (MDM2), a major inhibitor of the tumor suppressor p53. Overexpression of MTBP leads to p53-independent cell proliferation arrest, which is in turn blocked by simultaneous overexpression of MDM2. Importantly, reduced expression of MTBP in mice increases tumor metastasis and enhances migratory potential of mouse embryonic fibroblasts regardless of the presence of p53. Clinically, loss of MTBP expression in head and neck squamous cell carcinoma is associated with reduced patient survival, and is shown to serve as an independent prognostic factor when p53 is mutated in tumors. These results indicate the involvement of MTBP in suppressing tumor progression. Our recent findings demonstrate that overexpression of MTBP in human osteosarcoma cells lacking wild-type p53 inhibits metastasis, but not primary tumor growth, when cells are transplanted in femurs of immunocompromised mice. These data indicate that MTBP functions as a metastasis suppressor independent of p53 status. Furthermore, overexpression of MTBP suppresses cell migration and filopodia formation, in part, by inhibiting function of an actin crosslinking protein α-actinin-4. Thus, increasing evidence indicates the significance of MTBP in tumor progression. We summarize published results related to MTBP function and discuss caveats and future directions in this review article.
    CANCER AND METASTASIS REVIEW 06/2012; 31(3-4):633-40. DOI:10.1007/s10555-012-9364-x · 7.23 Impact Factor
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    ABSTRACT: Murine double minute (MDM2) binding protein (MTBP) has been implicated in cancer progression. Here, we demonstrate one mechanism by which MTBP inhibits cancer metastasis. Overexpression of MTBP in human osteosarcoma cell lines lacking wild-type p53 did not alter primary tumor growth in mice, but significantly inhibited metastases. MTBP downregulation increased the migratory potential of MDM2(-/-)p53(-/-) mouse embryonic fibroblasts, suggesting that MTBP inhibited cell migration independently of the Mdm2-p53 pathway. Co-immunoprecipitation and mass spectrometric analysis identified alpha-actinin-4 (ACTN4) as an MTBP-interacting protein. Endogenous MTBP interacted with and partially colocalized with ACTN4. MTBP overexpression inhibited cell migration and filopodia formation mediated by ACTN4. Increased cell migration by MTBP downregulation was inhibited by concomitant downregulation of ACTN4. MTBP also inhibited ACTN4-mediated F-actin bundling. We furthermore demonstrated that nuclear localization of MTBP was dispensable for inhibiting ACTN4-mediated cell migration and filopodia formation. Thus, MTBP suppresses cell migration, at least partially, by inhibiting ACTN4 function. Our study not only provides a mechanism of metastasis suppression by MTBP, but also suggests MTBP as a potential biomarker for cancer progression.Oncogene advance online publication, 27 February 2012; doi:10.1038/onc.2012.69.
    Oncogene 02/2012; 32(4). DOI:10.1038/onc.2012.69 · 8.46 Impact Factor
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    R Kibe · S Zhang · D Guo · L Marrero · F Tsien · P Rodriguez · S Khan · A Zieske · J Huang · W Li · S K Durum · T Iwakuma · Y Cui ·
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    ABSTRACT: Interleukin-7 (IL-7) is an essential T-cell survival cytokine. IL-7 receptor (IL-7Rα) deficiency severely impairs T-cell development due to substantial apoptosis. We hypothesized that IL-7Rα(null)-induced apoptosis is partially contributed by an elevated p53 activity. To investigate the genetic association of IL-7/IL-7Rα signaling with the p53 pathway, we generated IL-7Rα(null)p53(null) (DKO) mice. DKO mice exhibited a marked reduction of apoptosis in developing T cells and an augmented thymic lymphomagenesis with telomere erosions and exacerbated chromosomal anomalies, including chromosome duplications, breaks, and translocations. In particular, Robertsonian translocations, in which telocentric chromosomes fuse at the centromeric region, and a complete loss of telomeres at the fusion site occurred frequently in DKO thymic lymphomas. Cellular and molecular investigations revealed that IL-7/IL-7Rα signaling withdrawal diminished the protein synthesis of protection of telomere 1 (POT1), a subunit of telomere protective complex shelterin, leading to telomere erosion and the activation of the p53 pathway. Blockade of IL-7/IL-7Rα signaling in IL-7-dependent p53(null) cells reduced POT1 expression and caused telomere and chromosome abnormalities similar to those observed in DKO lymphomas. This study underscores a novel function of IL-7/IL-7Rα during T-cell development in regulating telomere integrity via POT1 expression and provides new insights into cytokine-mediated survival signals and T-cell lymphomagenesis.
    Cell death and differentiation 01/2012; 19(7):1139-51. DOI:10.1038/cdd.2011.203 · 8.18 Impact Factor
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    ABSTRACT: Mdm2 and Mdm4 are homologous RING domain-containing proteins that negatively regulate the tumor suppressor p53 under physiological and stress conditions. The RING domain of Mdm2 encodes an E3-ubiquitin ligase that promotes p53 degradation. In addition, Mdm2 and Mdm4 interact through their respective RING domains. The in vivo significance of Mdm2-Mdm4 heterodimerization in regulation of p53 function is unknown. In this study, we generated an Mdm4 conditional allele lacking the RING domain to investigate its role in Mdm2 and p53 regulation. Our results demonstrate that homozygous deletion of the Mdm4 RING domain results in prenatal lethality. Mechanistically, Mdm2-Mdm4 heterodimerization is critical for inhibiting lethal p53 activation during early embryogenesis. However, Mdm2-Mdm4 interaction is dispensable for regulating p53 activity as well as the stability of Mdm2 and p53 at later stages of development. We propose that Mdm4 is a key cofactor of Mdm2 that inhibits p53 activity primarily during early embryogenesis but is dispensable for regulating p53 and Mdm2 stability in the adult mouse.
    Proceedings of the National Academy of Sciences 07/2011; 108(29):11995-2000. DOI:10.1073/pnas.1102241108 · 9.67 Impact Factor
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    ABSTRACT: Emerging evidence suggests that the tumor suppressor p53 is also a crucial regulator for many physiological processes. Previous observations indicate that p53 suppresses inflammation by inhibiting inflammatory antigen-presenting cells. To investigate the potential role of p53 in autoimmune effector T cells, we generated p53(null)CD45.1 mice by crossing p53(null)CD45.2 and CD45.1 mice. We demonstrate that p53(null)CD45.1 mice spontaneously developed autoimmunity, with a significant increase in IL-17-producing Th17 effectors in their lymph nodes (4.7 ± 1.0%) compared to the age-matched counterparts (1.9 ± 0.8% for p53(null)CD45.2, 1.1 ± 0.2% for CD45.1, and 0.5 ± 0.1% for CD45.2 mice). Likewise, p53(null)CD45.1 mice possess highly elevated serum levels of inflammatory cytokines IL-17 and IL-6. This enhanced Th17 response results largely from an increased sensitivity of p53(null)CD45.1 T cells to IL-6-induced STAT3 phosphorylation. Administration of STAT3 inhibitor S31-201 (IC50 of 38.0 ± 7.2 μM for IL-6-induced STAT3 phosphorylation), but not PBS control, to p53(null)CD45.1 mice suppressed Th17 effectors and alleviated autoimmune pathology. This is the first report revealing that p53 activity in T cells suppresses autoimmunity by controlling Th17 effectors. This study suggests that p53 serves as a guardian of immunological functions and that the p53-STAT3-Th17 axis might be a therapeutic target for autoimmunity.
    The FASEB Journal 04/2011; 25(7):2387-98. DOI:10.1096/fj.10-175299 · 5.04 Impact Factor
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    ABSTRACT: The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a protein complex involved in embryonic development, is implicated in cell cycle regulation and the DNA damage response. Its role in tumor development, however, remains unclear. Here, we have shown that the COP9 subunit 6 (CSN6) gene is amplified in human breast cancer specimens, and the CSN6 protein is upregulated in human breast and thyroid tumors. CSN6 expression positively correlated with expression of murine double minute 2 (MDM2), a potent negative regulator of the p53 tumor suppressor. Expression of CSN6 appeared to prevent MDM2 autoubiquitination at lysine 364, resulting in stabilization of MDM2 and degradation of p53. Mice in which Csn6 was deleted died early in embryogenesis (E7.5). Embryos lacking both Csn6 and p53 survived to later in embryonic development (E10.5), which suggests that loss of p53 could partially rescue the effect of loss of Csn6. Mice heterozygous for Csn6 were sensitized to γ-irradiation-induced, p53-dependent apoptosis in both the thymus and the developing CNS. These mice were also less susceptible than wild-type mice to γ-irradiation-induced tumorigenesis. These results suggest that loss of CSN6 enhances p53-mediated tumor suppression in vivo and that CSN6 plays an important role in regulating DNA damage-associated apoptosis and tumorigenesis through control of the MDM2-p53 signaling pathway.
    The Journal of clinical investigation 03/2011; 121(3):851-65. DOI:10.1172/JCI44111 · 13.22 Impact Factor
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    N Agarwal · Y Tochigi · A S Adhikari · S Cui · Y Cui · T Iwakuma ·
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    ABSTRACT: Murine double minute 2 (MDM2) binding protein (MTBP) has been implicated in tumor cell proliferation, but the underlying mechanisms remain unclear. The results of MTBP expression analysis during cell cycle progression demonstrated that MTBP protein was rapidly degraded during mitosis. Immunofluorescence studies revealed that a portion of MTBP was localized at the kinetochores during prometaphase. MTBP overexpression delayed mitotic progression from nuclear envelope breakdown (NEB) to anaphase onset and induced abnormal chromosome segregation such as lagging chromosomes, chromosome bridges, and multipolar chromosome segregation. Conversely, MTBP downmodulation caused an abbreviated metaphase and insufficient mitotic arrest, resulting in abnormal chromosome segregation, aneuploidy, decreased cell proliferation, senescence, and cell death, similar to that of Mad2 (mitotic arrest-deficient 2) downmodulation. Furthermore, MTBP downmodulation inhibited the accumulation of Mad1 and Mad2, but not BubR1 (budding uninhibited by benzimidazoles related 1), on the kinetochores, whereas MTBP overexpression inhibited the release of Mad2 from the metaphase kinetochores. These results may imply that MTBP has an important role in recruiting and/or retaining the Mad1/Mad2 complex at the kinetochores during prometaphase, but its degradation is required for silencing the mitotic checkpoint. Together, this study indicates that MTBP has a crucial role in proper mitotic progression and faithful chromosome segregation, providing new insights into regulation of the mitotic checkpoint.
    Cell death and differentiation 01/2011; 18(7):1208-19. DOI:10.1038/cdd.2010.189 · 8.18 Impact Factor
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    Amit S Adhikari · Neeraj Agarwal · Tomoo Iwakuma ·
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    ABSTRACT: The lethality of cancer is mainly caused by its properties of metastasis, drug resistance, and subsequent recurrence. Understanding the mechanisms governing these properties and developing novel strategies to overcome them will greatly improve the survival of cancer patients. Recent findings suggest that tumors are comprised of heterogeneous cell populations, and only a small fraction of these are tumorigenic with the ability to self-renew and produce phenotypically diverse tumor cell populations. Cells in this fraction are called tumor-initiating cells (TICs) or cancer stem cells (CSCs). TICs have been identified from many types of cancer. They share several similarities with normal adult stem cells including sphere-forming ability, self-renewability, and expression of stem cell surface markers and transcription factors. TICs have also been proposed to be responsible for cancer metastasis, however, scarce evidence for their metastatic potential has been provided. In this review article, we have attempted to summarize the studies which have examined the metastatic potential of TICs in solid tumors.
    Frontiers in Bioscience 01/2011; 16:1927-38. · 3.52 Impact Factor

Publication Stats

1k Citations
297.28 Total Impact Points


  • 2012-2015
    • University of Kansas
      Lawrence, Kansas, United States
    • Kansas City VA Medical Center
      Kansas City, Missouri, United States
  • 2007-2012
    • Louisiana State University Health Sciences Center New Orleans
      • • Department of Genetics
      • • Stanley S. Scott Cancer Center
      New Orleans, Louisiana, United States
  • 2004-2008
    • University of Texas MD Anderson Cancer Center
      • Human and Molecular Genetics
      Houston, Texas, United States
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States