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Differentiation

NF-κB (p65/RelA) as a regulator of TNFα-mediated ML-1 cell differentiation

Leukemia volume 15, pages 808–813 (2001)Cite this article

Abstract

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-α (TNF-α). Induction of differentiation, but not of proliferation, involved the selective activation of diverse members of the NF-κB family of proteins. In differentiation-induced cells, NF-κB (p65) was translocated from the cytoplasm to the nucleus, whereas NF-κB (p75) remained localized to the cytoplasm. In contrast, NF-κB (p52) was present in the nuclei of proliferation- as well as of differentiation-induced ML-1 cells. The differentiation-specific translocation of NF-κB (p65) from the cytoplasm to the nucleus was mediated by an increase in the level of NIK, the NF-κB-inducing kinase which, through phosphorylation of IκB kinase α (Iκkα), causes a decrease in the level of IκBα, 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.

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Acknowledgements

This study was aided by grant CA-36241 from the National Cancer Institute, DHHS, and by a grant from the Roswell Park Alliance Foundation. We are grateful to Asahi Chemical Co., Tokyo, Japan for supplying TNFα. We also thank Dr Guillermina Lozano of the MD Anderson Cancer Institute, Houston,TX for providing the p53 CAT construct.

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  1. Department of Molecular Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

    A Mudipalli, Z Li, R Hromchak & A Bloch

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  1. A Mudipalli
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Mudipalli, A., Li, Z., Hromchak, R. et al. NF-κB (p65/RelA) as a regulator of TNFα-mediated ML-1 cell differentiation. Leukemia 15, 808–813 (2001). https://doi.org/10.1038/sj.leu.2402083

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