Neurokinin-A inhibits cell cycle activators in K562 cells and activates Smad 4 through a non-canonical pathway: A novel method in neural-hematopoietic axis

作者：Ricardo Michael; Trzaska Katarzyna A; Rameshwar Pranela^*

来源：Journal of Neuroimmunology, 2008, 204(1-2): 85-91.

DOI：10.1016/j.jneuroim.2008.07.013

• Neurokinin-A
• Neurokinin-2
• TGF-beta 1
• Hematopoiesis
• Smad 4
• Cell cycle
• TGF-beta

Hematopoiesis is a complex process in which blood and immune cells are developed. Among the regulators of hematopoiesis are two members of the G-protein coupled receptor family, neurokinin-1 (NK1) and NK2, which partly encompass the communication between the neural and hematopoietic systems. This communication also involves a complex network of cytokines, and crosstalk between NK1 and NK2. Excessive activation of NK1 has been linked to leukemia. NK2 exerts negative effects on NK1. Previous studies with the hematopoietic progenitor cell line, K562 have identified activated p53 as a mediator of NK2 transcription. which correlated with cell proliferation. This study investigated the mechanism of NK-A mediated inhibition of cell proliferation. K562 was stimulated with 10 nM of NK-A, and the nuclear extracts were analyzed by Western blots for cell cycle regulators. The studies showed decreases in the cell cycling activators, Cdk2 and Cyclin A, which correlated with increases in p21 and p53. The differentiation protein p19 was unchanged, suggesting that NK-A maintains K562 at cell cycle checkpoints, but does not have roles in differentiation. NK-A appears to regulate TGF-beta 1 production at the level of translation, Despite the production of TGF-beta 1, the activation of Smad 4 occurs by NK-A, via a non-canonical pathway, as indicated by an inhibitor of TGF-beta receptor activators, SB431542. TGF-beta 1 was needed to prevent exacerbated decrease in Cyclin A, but not Cdk2, indicating that it was its role might be limited to balancing the negative regulation of TGF-beta 1. In summary, NK-A enhances translation of TGF-beta 1 in K562 cells. NK-A suppressed cell cycle activators, and activated Smad 4 via a non-canonical pathway, independent of TGF-beta receptor. These findings are significant in the negative regulation of progenitor proliferation, with implications for hematopoiesis and its associated dysfunctions.

• 出版日期2008-11-15