1alpha,25-dihydroxyvitamin D3 and bryostatin-1 synergize to induce monocytic differentiation of NB4 cells

In this thesis, it is shown that Bryostatin-1, in combination with 1,25(OH) ₂D₃ is a weaker inducer of monocytic differentiation of NB4 cells than is the phorbol ester, TPA. Changes in the cell cycle traverse occur with 1,25(OH)₂D₃ and Bryo treatment, including altered expression of the cell cycle regulatory proteins Cdk1, Cdk2, Cdk4 and RBBP.; The priming effect of 1,25(OH)₂D₃ in the maturation of NB4 cells involves NFκB signaling triggered by IκBα, phosphorylation. Over a 12 h time course, 1,25(OH)₂D₃ does not significantly affect the expression of IκBα. NB4 cells exhibit an elevated constitutive activity of IKKα, but this is not the kinase responsible for the rapid phosphorylation of IκBα induced by 1,25(OH)₂D₃. Thus, 1,25(OH)₂D₃ clearly primes NB4 cells for monocytic differentiation in response to either Bryo or TPA, but the mechanism by which these agents recruit the NFκB signaling pathway and promote cell cycle arrest remain unclear.