Regulation of Cop9 signalosome activity by the EF-hand Ca2+-binding protein tescalcin

Abstract

Ca2+-binding protein tescalcin is known to be involved in hematopoietic cell differentiation, however this mechanism is poorly understood. Here we identified a novel binding partner of tescalcin, the subunit 4 of COP9 signalosome (CSN), a multiprotein complex essential for the development of all eukaryotes. This interaction is selective, Ca2+-dependent, and involves the PCI domain of the CSN4 subunit. We then investigated tescalcin and CSN activity in human erythroleukemia HEL and promyelocytic leukemia K562 cells. We found that PMA-induced differentiation resulting in the upregulation of tescalcin coincides with reduced deneddylation of Cullin-1 (Cul1) and stabilization of p27Kip1, molecular events associated with CSN activity. The knockdown of tescalcin led to an increase in Cul1 deneddylation, expression of F-box protein Skp2 and transcription factor c-Jun, while the levels of cell cycle regulators p27Kip1 and p53 decreased. These effects are consistent with the hypothesis that tescalcin may play a role of a negative regulator of CSN activity towards Cul1 in the process of induced cell differentiation.