Human calcium/calmodulin-dependent serine protein kinase regulates the expression of p21 via the E2A transcription factor.

CASK (calcium/calmodulin-dependent serine protein kinase) is a kind of scaffolding protein that recruits or organizes other proteins at the plasma membrane to co-ordinate signal transduction pathways within the cytoplasm and nucleus. We have previously found that hCASK (human CASK) binds Id1 (inhibitor of DNA binding 1) through hCASK's GUK (guanylate kinase) domain and inhibits cell growth, probably via interactions with Id1. Overexpression of hCASK resulted in a reduced rate of cell growth, although inhibition of CASK via RNAi (RNA interference) promoted cell proliferation in ECV304 cells. This study revealed that hCASK regulates the protein and mRNA level of p21(wafi/cip1) (referred to throughout as p21), and activated the expression of p21 in a time-dependent manner. Two E-boxes in the proximal region at the TSS (transcription start site) play key roles in regulating hCASK-mediated p21 expression. We suggest that E2A (E12 and E47), a representative of the E proteins that binds the E-box elements, is a participant in the mediation of p21 expression by hCASK. The results of the present study suggest that hCASK regulation of cell growth might involve p21 expression, and that the bHLH (basic helix-loop-helix) transcription factor E2A probably participates in hCASK regulation of p21 expression. From these findings, we propose a novel proliferation signalling pathway mediated by hCASK.