An Intact NF-κB Pathway is Required for Histone Deacetylase Inhibitor-Induced G1 Arrest and Maturation in U937 Human Myeloid Leukemia Cells

被引:30
|
作者
Dai, Yun [1 ]
Rahmani, Mohamed [1 ]
Grant, Steven [1 ,2 ,3 ]
机构
[1] Virginia Commonwealth Univ, Med Coll Virginia, Dept Med, Div Hematol Oncol, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Med Coll Virginia, Dept Biochem, Richmond, VA 23298 USA
[3] Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol, Richmond, VA 23298 USA
关键词
leukemia; histone deacetylase inhibitor; NF-kappa B; differentiation; G(1) arrest;
D O I
10.4161/cc.2.5.465
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The role of NF-kappa B in regulating G1 arrest and maturation induced by the histone deacetylase inhibitor sodium butyrate (NaB) was examined in human myelomonocytic leukemia cells (U937). Cells stably transfected with an I kappa B alpha "super-repressor" lacking phosphorylation sites necessary for proteasomal degradation exhibited diminished I kappa B alpha phosphorylation and NF-kappa B DNA binding upon exposure to TNF alpha. When exposed to NaB (1 mM; 48 hr) or PMA (5 nM; 24 hr), I kappa B alpha M cells displayed a marked reduction in G(1) arrest compared to Neo controls. In each case, this was accompanied by a significant reduction in the percentage of cells expressing the differentiation markers CD11a, CD11b, and CD18. The impairment in NaB-induced maturation in mutant cells was associated with a reciprocal increase in apoptosis. In contrast to impairment in NaB- or PMA-induced NF-kappa B DNA binding, stable expression of the I.BaM did not modify DNA binding of SP1 or AP2 transcription factors. I kappa B alpha M cells also displayed impairment in NaB- and PMA-mediated induction of p21(CIP1) and phosphorylation (inactivation) of p34(cdc2), as well as diminished levels of pRb-bound E2F1. Finally, the NF-kappa B inhibitor CAPE antagonized NaB- and PMA-related NF-kappa B DNA binding as well as induction of p21(CIP1). Together, these findings suggest that NF-kappa B plays an important functional role in mediating NaB-induced p21(CIP1) induction, G1 arrest, and maturation in human myelomonocytic leukemia cells, and that disruption of the NF-kappa B pathway causes cells to engage an alternative, apoptotic program.
引用
收藏
页码:467 / 472
页数:6
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