ML-1 human myeloblastic leukemia cells, suspended in serum-depleted medium,
proliferate when the insulin-like growth factor-1 (IGF-I) and transferrin
(Tf) are supplied, but differentiate to monocytes when these factors are re
placed by the tumor necrosis factor-alpha (TNF-alpha). Induction of differe
ntiation, but not of proliferation, involved the selective activation of di
verse members of the NF-kappaB family of proteins. In differentiation-induc
ed cells, NF-kappaB (p65) was translocated from the cytoplasm to the nucleu
s, whereas NF-kappaB (p75) remained localized to the cytoplasm. In contrast
, NF-kappaB (p52) was present in the nuclei of proliferation- as well as of
differentiation-induced ML-1 cells. The differentiation-specific transloca
tion of NF-kappaB (p65) from the cytoplasm to the nucleus was mediated by a
n increase in the level of NIK, the NF-kappaB-inducing kinase which, throug
h phosphorylation of I kappaB kinase alpha (I kappak alpha), causes a decre
ase in the level of I kappaB alpha, allowing p65 to move from the cytoplasm
to the nucleus. The p52/p65 heterodimer formed in the nucleus, bound speci
fically to the promoter of the tumor suppressor protein p53, effecting a 25
to 30-fold increase in the level of this protein. As we reported previousl
y (Li et al, Cancer Res 1998; 58: 4282-4287), that increase led to the decr
eased expression of proliferating cell nuclear antigen (PCNA) and to the lo
ss of proliferation-associated DNA synthesis. The ensuing uncoupling of gro
wth from differentiation was followed by the initiation of the monocyte-spe
cific differentiation program.