NF-kappaB (p65/RelA) as a regulator of TNFalpha-mediated ML-1 cell differentiation.
ML-1 human myeloblastic leukemia cells, suspended in serum-depleted medium, proliferate when the insulin-like growth factor-1 (IGF-1) and transferrin (Tf) are supplied, but differentiate to monocytes when these factors are replaced by the tumor necrosis factor-alpha (TNF-alpha). Induction of differentiation, but not of proliferation, involved the selective activation of diverse members of the NF-kappaB family of proteins. In differentiation-induced cells, NF-kappaB (p65) was translocated from the cytoplasm to the nucleus, 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 translocation of NF-kappaB (p65) from the cytoplasm to the nucleus was mediated by an increase in the level of NIK, the NF-kappaB-inducing kinase which, through phosphorylation of IkappaB kinase alpha (Ikappakalpha), causes a decrease in the level of IkappaBalpha, allowing p65 to move from the cytoplasm to the nucleus. The p52/p65 heterodimer formed in the nucleus, bound specifically 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 previously (Li et al, Cancer Res 1998; 58: 4282-4287), that increase led to the decreased expression of proliferating cell nuclear antigen (PCNA) and to the loss of proliferation-associated DNA synthesis. The ensuing uncoupling of growth from differentiation was followed by the initiation of the monocyte-specific differentiation program.
Mudipalli
A
A
Department of Molecular Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Li
Z
Z
Hromchak
R
R
Bloch
A
A
D002454:Cell Differentiation; D002455:Cell Division; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53