1[alpha],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 NF[kappa]B signaling triggered by I[kappa]B[alpha], phosphorylation. Over a 12 h time course, 1,25(OH)2D3 does not significantly affect the expression of I[kappa]B[alpha]. NB4 cells exhibit an elevated constitutive activity of IKK[alpha], but this is not the kinase responsible for the rapid phosphorylation of I[kappa]B[alpha] 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 NF[kappa]B signaling pathway and promote cell cycle arrest remain unclear.