VDUP1 signaling in immune and cancer cells

다국어 초록 (Multilingual Abstract)

Vitamin D₃ up-regulated protein 1(VDUP1) is a stress-response gene which is up-regulated by 1,25(OH)₂D₃ in many cells. In tumor tissues, the expression of VDUP1 was reduced as compared to normal controls. Upon stimulation by growth-inhibitory signals such as TGF-β1 and 1,25(OH)₂D₃, its expression was rapidly up-regulated as the cell growth was retarded. The transfection of VDUP1 in tumor cells reduced cell growth. The VDUP1 expression was also increased when the cell-cycle progression was arrested. Transfection of VDUP1 induced cell-cycle arrest at the G0/G1 phase, indicating that VDUP1 possesses a tumor-suppressive activity. The in vivo roles of VDUP1 were investigated by producing mice lacking VDUP1(VDUP1^(-/-) mice). Here, we demonstrate that VDUP1^(-/-) mice showed severe lymphoid hyperplasia in the small intestine and increased tumor susceptibility to carcinogen. VDUP1^(-/-) mice had a profound reduction in the numbers of NK cells. In addition, these mice showed decreased NK activity and reduced CD122 expression. Meanwhile, we found that VDUP1^(-/-) fibroblast cells proliferated more compared to wild-type cells with reduced expression of p27^(kip1), a cyclin-dependent kinase inhibitor. Jab1 is known to interact with p27^(kip1) and to decrease the stability of p27^(kip1). VDUP1 interacted with jab1 and restored jab1-induced suppression of p27^(kip1) stability. In this process, VDUP1 blocked the jab1-mediated translocation of p27^(kip1) from the nucleus to the cytoplasm. In addition, VDUP1 inhibited jab1-mediated AP-1 activation and cell proliferation. Taken together, these results indicate that VDUP1 is a novel factor for the tumorigenesis and NK maturation in vivo.