Takao Ito

All Publications

• Yorkie drives Ras-induced tumor progression by microRNA-mediated inhibition of cellular senescence SCIENCE SIGNALING Ito, T., Igaki, T. 2021; 14 (685)

  Abstract

  The activation of Ras signaling is a major early event of oncogenesis in many contexts, yet paradoxically, Ras signaling induces cellular senescence, which prevents tumorigenesis. Thus, Ras-activated cells must overcome senescence to develop into cancer. Through a genetic screen in Drosophila melanogaster, we found that the ETS family transcriptional activator Pointed (Pnt) was necessary and sufficient to trigger cellular senescence upon Ras activation and blocked Ras-induced tumor growth in eye-antennal discs. Through analyses of mosaic discs using various genetic tools, we identified a mechanism of tumor progression in which loss of cell polarity, a common driver of epithelial oncogenesis, abrogated Ras-induced cellular senescence through microRNA-mediated inhibition of Pnt. Mechanistically, polarity defects in Ras-activated cells caused activation of the Hippo effector Yorkie (Yki), which induced the expression of the microRNA bantam bantam-mediated repression of the E3 ligase-associated protein Tribbles (Trbl) relieved Ras- and Akt-dependent inhibition of the transcription factor FoxO. The restoration of FoxO activity in Ras-activated cells induced the expression of the microRNAs miR-9c and miR-79, which led to reduced pnt expression, thereby abrogating cellular senescence and promoting tumor progression. Our findings provide a mechanistic explanation for how Ras-activated tumors progress toward malignancy by overcoming cellular senescence.

  View details for DOI 10.1126/scisignal.aaz3578

  View details for Web of Science ID 000658258100001

  View details for PubMedID 34074704

• Dissecting cellular senescence and SASP in Drosophila INFLAMMATION AND REGENERATION Ito, T., Igaki, T. 2016; 36: 25

  Abstract

  Cellular senescence can act as both tumor suppressor and tumor promoter depending on the cellular contexts. On one hand, premature senescence has been considered as an innate host defense mechanism against carcinogenesis in mammals. In response to various stresses including oxidative stress, DNA damage, and oncogenic stress, suffered cells undergo irreversible cell cycle arrest, leading to tumor suppression. On the other hand, recent studies in mammalian systems have revealed that senescent cells can drive oncogenesis by secreting diverse proteins such as inflammatory cytokines, matrix remodeling factors, and growth factors, the phenomenon called senescence-associated secretory phenotype (SASP). However, the mechanisms by which these contradictory effects regulate tumor growth and metastasis in vivo have been elusive. Here, we review the recent discovery of cellular senescence in Drosophila and the mechanisms underlying senescence-mediated tumor regulation dissected by Drosophila genetics.

  View details for DOI 10.1186/s41232-016-0031-4

  View details for Web of Science ID 000449587700025

  View details for PubMedID 29259698

  View details for PubMedCentralID PMC5725765

• Inhibitory Mechanism of FAT4 Gene Expression in Response to Actin Dynamics during Src-Induced Carcinogenesis PLOS ONE Ito, T., Taniguchi, H., Fukagai, K., Okamuro, S., Kobayashi, A. 2015; 10 (2): e0118336

  Abstract

  Oncogenic transformation is characterized by morphological changes resulting from alterations in actin dynamics and adhesive activities. Emerging evidence suggests that the protocadherin FAT4 acts as a tumor suppressor in humans, and reduced FAT4 gene expression has been reported in breast and lung cancers and melanoma. However, the mechanism controlling FAT4 gene expression is poorly understood. In this study, we show that transient activation of the Src oncoprotein represses FAT4 mRNA expression through actin depolymerization in the immortalized normal human mammary epithelial cell line MCF-10A. Src activation causes actin depolymerization via the MEK/Erk/Cofilin cascade. The MEK inhibitor U0126 blocks the inhibitory effect of Src on FAT4 mRNA expression and Src-induced actin depolymerization. To determine whether actin dynamics act on the regulation of FAT4 mRNA expression, we treated MCF-10A cells with the ROCK inhibitor Y-27632. Y-27632 treatment decreased FAT4 mRNA expression. This suppressive effect was blocked by siRNA-mediated knockdown of Cofilin1. Furthermore, simultaneous administration of Latrunculin A (an actin depolymerizing agent), Y-27632, and Cofilin1 siRNA to the cells resulted in a marked reduction of FAT4 mRNA expression. Intriguingly, we also found that FAT4 mRNA expression was reduced under both low cell density and low stiffness conditions, which suggests that mechanotransduction affects FAT4 mRNA expression. Additionally, we show that siRNA-mediated FAT4 knockdown induced the activity of the Hippo effector YAP/TAZ in MCF-10A cells. Taken together, our results reveal a novel inhibitory mechanism of FAT4 gene expression through actin depolymerization during Src-induced carcinogenesis in human breast cells.

  View details for DOI 10.1371/journal.pone.0118336

  View details for Web of Science ID 000350682600119

  View details for PubMedID 25679223

  View details for PubMedCentralID PMC4334522

• The Casein Kinase 2-Nrf1 Axis Controls the Clearance of Ubiquitinated Proteins by Regulating Proteasome Gene Expression MOLECULAR AND CELLULAR BIOLOGY Tsuchiya, Y., Taniguchi, H., Ito, Y., Morita, T., Karim, M., Ohtake, N., Fukagai, K., Ito, T., Okamuro, S., Iemura, S., Natsume, T., Nishida, E., Kobayashi, A. 2013; 33 (17): 3461-3472

  Abstract

  Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of human diseases, including neurodegenerative disorders. Thus, stimulating proteasome activity is a promising strategy to ameliorate these age-related diseases. Here we show that the protein kinase casein kinase 2 (CK2) regulates the transcriptional activity of Nrf1 to control the expression of the proteasome genes and thus the clearance of ubiquitinated proteins. We identify CK2 as an Nrf1-binding protein and find that the knockdown of CK2 enhances the Nrf1-dependent expression of the proteasome subunit genes. Real-time monitoring of proteasome activity reveals that CK2 knockdown alleviates the accumulation of ubiquitinated proteins upon proteasome inhibition. Furthermore, we identify Ser 497 of Nrf1 as the CK2 phosphorylation site and demonstrate that its alanine substitution (S497A) augments the transcriptional activity of Nrf1 and mitigates proteasome dysfunction and the formation of p62-positive juxtanuclear inclusion bodies upon proteasome inhibition. These results indicate that the CK2-mediated phosphorylation of Nrf1 suppresses the proteasome gene expression and activity and thus suggest that the CK2-Nrf1 axis is a potential therapeutic target for diseases associated with UPS impairment.

  View details for DOI 10.1128/MCB.01271-12

  View details for Web of Science ID 000322817600006

  View details for PubMedID 23816881

  View details for PubMedCentralID PMC3753846