Down-regulation of TRRAP-dependent hTERT and TRRAP-independent CAD activation by Myc/Max contributes to the differentiation of HL60 cells after exposure to DMSO.
Myc/Max/Mad often play pivotal roles in the proliferation, apoptosis, differentiation and cell cycle progress of leukemia cells. Myc and Mad are known to be unstable proteins and their expression is tightly regulated throughout cell cycle progression and differentiation. Usually, c-Myc expression is implicated in cell growth and proliferation, and the deregulated expression of c-Myc in both myeloid leukemia cells and normal myeloid cells not only blocks terminal differentiation but also its associated growth arrest. HL60 cells could be induced to differentiate into mature granulocytes by DMSO in vitro, but the mechanism of this effect has not been elucidated clearly. We proposed the hypothesis that down-regulation of c-Myc expression by DMSO contributed to the differentiation of HL60 cells by way of activating target genes hTert and CAD. The results showed that c-Myc expression was down-regulated in differentiated HL60 cells but not in exponentially-growing HL60 cells, without or with the target gene activation of hTert and CAD, respectively. Further study indicated that hTert activation is TRRAP-dependent while CAD activation is TRRAP-independent. On the other hand, up-regulation of P(21) and P(27) and down-regulation of cyclinA and cyclinE also play important roles in induction of the terminal differentiation of HL60 cells. Our results support the hypothesis that c-Myc expression and activation of target genes for hTert and CAD play critical roles in the proliferation of HL60 cells, while down-regulation of c-Myc expression and activation of target genes for hTert and CAD contributed to the terminal differentiation of HL60 cells after exposure to DMSO in vitro.