게시판

Principal Investigator
- Inpyo Choi, Ph.D, Immunotherapy Research Center / July 2013

R&D Background
- Hematopoietic cells are vulnerable to oxidative stress, and malignancy of hematopoietic tissues is observed in the presence of chronic oxidative stress. Homeostatic regulation of redox status in hematopoietic tissues is important for normal hematopoiesis. Oxidative stress occurs mainly due to excessive accumulation of cellular reactive oxygen species or deficiency of antioxidant defense system. Oxidative stress often leads to pathologic diseases such as diabetes, neurodegenerative diseases, and cancer. There is growing evidence that balanced regulation of ROS is critical for hematopoiesis. Thioredoxin-interacting protein (TXNIP) is a 397 amino acid, 50 kDa protein that belongs to the arrestin family, and Txnip knock-out (KO) mice show a high incidence of hepatocellular carcinoma. TXNIP expression is reduced in many types of tumors, and TXNIP overexpression inhibits tumor growth by blocking cell-cycle progression. The numbers of natural killer cells in the bone marrow of Txnip KO mice are reduced, and the long-term reconstituting HSC population shows an exhausted phenotype and is reduced in frequency. In this study, we demonstrate that Txnip KO hematopoietic cells had defects in the regulation of ROS levels and were more sensitive than wild-type cells to oxidative stress. We also demonstrated that TXNIP exerted its antioxidant effects in hematopoietic cells by stabilizing p53 under oxidative stress. Our findings suggest that TXNIP plays a critical role in the antioxidant defense mechanisms of hematopoietic cells by activating the p53 pathway during oxidative stress.

Research Summary
- TXNIP, which is induced by oxidative stress, is a known regulator of intracellular ROS. Txnip KO old mice exhibited elevated ROS levels in hematopoietic cells and showed a reduction in hematopoietic cell population. Loss of TXNIP led to a dramatic reduction of mouse survival under oxidative stress. TXNIP directly regulated p53 protein by interfering with p53- mouse double minute 2 interactions and increasing p53 transcriptional activity. Txnip KO mice showed downregulation of the antioxidant genes induced by p53. Introduction of TXNIP or p53 into Txnip KO bone marrow cells rescued the HSC frequency and greatly increased survival in mice following oxidative stress. These data demonstrated that TXNIP gene is the factor associated with maintenance and generation of hematopoietic stem cells in the environment where the hematopoietic stem cells are aging or under stress. Overall, we identified that TXNIP gene increases or maintains the expression of p53, which is a tumour suppressor and anti-oxidant gene. According to their research, the TXNIP gene performs an important role of restricting decomposition of p53 by directly splicing with p53.
Applied Cases and Effects
- Through this research, we have laid out the basis for fundamental technology development to maintain homeostasis of hematopoietic stem cells and to regulate generation and differentiation of hematopoietic stem cells, based on the utilization of TXNIP gene. Going further, our research will offer key factors critical to the development of technologies for maintaining and generating hematopoietic stem cells as well as for cancer treatment and regulation of aging.




Principal Investigator Inpyo Choi, Ph.D, Immunotherapy Research Center / July 2013 R&D Background Hematopoietic cells are vulnerable to oxidative stress, and malignancy of hematopoietic tissues is observed in the presence of chronic oxidative stress. Homeostatic regulation of redox status in hematopoietic tissues is important for normal hematopoiesis. Oxidative stress occurs mainly due to excessive accumulation of cellular reactive oxygen species or deficiency of antioxidant defense system. Oxidative stress often leads to pathologic diseases such as diabetes, neurodegenerative diseases, and cancer. There is growing evidence that balanced regulation of ROS is critical for hematopoiesis. Thioredoxin-interacting protein (TXNIP) is a 397 amino acid, 50 kDa protein that belongs to the arrestin family, and Txnip knock-out (KO) mice show a high incidence of hepatocellular carcinoma. TXNIP expression is reduced in many types of tumors, and TXNIP overexpression inhibits tumor growth by blocking cell-cycle progression. The numbers of natural killer cells in the bone marrow of Txnip KO mice are reduced, and the long-term reconstituting HSC population shows an exhausted phenotype and is reduced in frequency. In this study, we demonstrate that Txnip KO hematopoietic cells had defects in the regulation of ROS levels and were more sensitive than wild-type cells to oxidative stress. We also demonstrated that TXNIP exerted its antioxidant effects in hematopoietic cells by stabilizing p53 under oxidative stress. Our findings suggest that TXNIP plays a critical role in the antioxidant defense mechanisms of hematopoietic cells by activating the p53 pathway during oxidative stress. Research Summary TXNIP, which is induced by oxidative stress, is a known regulator of intracellular ROS. Txnip KO old mice exhibited elevated ROS levels in hematopoietic cells and showed a reduction in hematopoietic cell population. Loss of TXNIP led to a dramatic reduction of mouse survival under oxidative stress. TXNIP directly regulated p53 protein by interfering with p53- mouse double minute 2 interactions and increasing p53 transcriptional activity. Txnip KO mice showed downregulation of the antioxidant genes induced by p53. Introduction of TXNIP or p53 into Txnip KO bone marrow cells rescued the HSC frequency and greatly increased survival in mice following oxidative stress. These data demonstrated that TXNIP gene is the factor associated with maintenance and generation of hematopoietic stem cells in the environment where the hematopoietic stem cells are aging or under stress. Overall, we identified that TXNIP gene increases or maintains the expression of p53, which is a tumour suppressor and anti-oxidant gene. According to their research, the TXNIP gene performs an important role of restricting decomposition of p53 by directly splicing with p53. Applied Cases and Effects Through this research, we have laid out the basis for fundamental technology development to maintain homeostasis of hematopoietic stem cells and to regulate generation and differentiation of hematopoietic stem cells, based on the utilization of TXNIP gene. Going further, our research will offer key factors critical to the development of technologies for maintaining and generating hematopoietic stem cells as well as for cancer treatment and regulation of aging.