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(1) Roles of stemness and cellular senescence in carcinogenesis
(1) Roles of stemness and cellular senescence in carcinogenesis
Stem cells are defined as undifferentiated cells that possess both multipotency and self-renewal capacity. For example, embryonic stem cells (ESCs) represent a typical type of stem cell. In addition, it is well established that adult tissues harbor undifferentiated stem cell populations, known as adult stem cells (ASCs), which play essential roles in maintaining tissue homeostasis.
Interestingly, cells with such “undifferentiated” properties are also found within cancer cell populations, and these stem cell–like cells are known to contribute to tumor aggressiveness.
We have previously established a unique metastatic gastric cancer model derived from ASCs and have investigated the molecular mechanisms underlying tumorigenesis. Our studies revealed that cancer cells derived from ASCs retain undifferentiated characteristics, and we identified key factors responsible for regulating their stemness.
We are currently investigating whether these factors could serve as novel targets for molecularly targeted therapies.
(2) Regulation of cellular phenotypes using partial reprogramming technologies
(2) Regulation of cellular phenotypes using partial reprogramming technologies
The process by which differentiated cells acquire undifferentiated properties is referred to as dedifferentiation. Since the discovery that cellular reprogramming can generate induced pluripotent stem cells (iPSCs), research on cellular plasticity has advanced significantly.
We have previously demonstrated that the application of reprogramming technologies can enhance tissue regenerative capacity and potentially suppress organismal aging in mice. Building upon these findings, we are conducting comprehensive molecular analyses of the effects of reprogramming and integrating these insights to develop strategies that promote “rejuvenation” at both the cellular and organismal levels.
Our ultimate goal is to establish approaches that can restore youthful functions in cells and organisms.
(3) Molecular mechanisms of MAPK signaling in the regulation of cell proliferation and function
(3) Molecular mechanisms of MAPK signaling in the regulation of cell proliferation and function
The MAPK cascade is an intracellular signaling pathway activated by stimuli such as growth factors and cellular stress, and it plays a crucial role in regulating cell proliferation, differentiation, and various cellular functions. To elucidate these signaling mechanisms, we are trying to identify and characterize target proteins (physiological substrates) of MAPKs.
We have identified Mnk as a protein kinase that is activated by MAPKs. Mnk is thought to regulate the initiation of protein translation, and we are currently investigating its regulatory mechanisms and physiological functions.
In addition, by utilizing multiplex gene knockout technology in cultured cells based on the CRISPR/Cas9 system, we are conducting comprehensive functional analyses of various signaling molecules within the MAPK pathway.
(4) Elucidation of the catalytic functions of phospholipid-hydrolyzing enzymes
(4) Elucidation of the catalytic functions of phospholipid-hydrolyzing enzymes
We have investigated phospholipid-hydrolyzing enzymes, particularly phospholipase A2 (PLA2), which is involved in the production of arachidonic acid—a precursor of the pain mediator prostaglandins—and sphingomyelinase (SMase), which is responsible for the generation of ceramide that induces apoptosis.
These enzymes were purified either from biological sources or from recombinant expression systems established in Escherichia coli, and were analyzed through a series of experiments based on enzyme kinetics. Our results revealed that PLA2 utilizes His48 as a catalytic residue, whereas SMase employs His296 as its catalytic residue.
Furthermore, we demonstrated that the enzymatic activities of both enzymes are regulated by various metal ions.
We are currently conducting detailed analyses of the catalytic mechanisms of these enzymes and plan to extend our studies to other phospholipid-hydrolyzing enzymes.
(5) Elucidation of the inhibitory mechanisms of phospholipid-hydrolyzing enzymes by inhibitors
(5) Elucidation of the inhibitory mechanisms of phospholipid-hydrolyzing enzymes by inhibitors
Phospholipid-hydrolyzing enzymes catalyze the hydrolysis of membrane phospholipids, leading to the production of a variety of biologically active molecules. Identification of compounds that inhibit these processes could contribute to the development of therapeutic agents, such as anti-inflammatory drugs.
Based on this concept, we are conducting studies to identify inhibitors of PLA2 and SMase. We have demonstrated that compounds structurally similar to PLA2 substrates can bind to the substrate-binding site of the enzyme and inhibit its activity.
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