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Molecular Mechanism of hTid-1, the Human Homolog of Drosophila Tumor Suppressor l(2)Tid, in the Regulation of NF-κB Activity and Suppression of Tumor Growth

Authors
  • Hua Cheng
  • Carlo Cenciarelli
  • Gina Nelkin
  • Rachel Tsan
  • Dominic Fan
  • Cecilia Cheng-Mayer
  • Isaiah J. Fidler
Publisher
American Society for Microbiology
Publication Date
Jan 01, 2005
Source
PMC
Keywords
Disciplines
  • Biology
License
Unknown

Abstract

hTid-1, a human homolog of the Drosophila tumor suppressor l(2)Tid and a novel DnaJ protein, regulates the activity of nuclear factor κB (NF-κB), but its mechanism is not established. We report here that hTid-1 strongly associated with the cytoplasmic protein complex of NF-κB-IκB through direct interaction with IκBα/β and the IKKα/β subunits of the IκB kinase complex. These interactions resulted in suppression of the IKK activity in a J-domain-dependent fashion and led to the cytoplasmic retention and enhanced stability of IκB. Overexpression of hTid-1 by using recombinant baculovirus or adenovirus led to inhibition of cell proliferation and induction of apoptosis of human osteosarcoma cells regardless of the p53 expression status. Adherent cultured cells transduced with Ad.hTid-1 detached from the dish surface. Morphological changes consistent with apoptosis and cell death were evident 48 h after Ad.EGFP-hTid-1 transduction. In contrast, cells transduced with Ad.EGFP or Ad.EGFP-hTd-1ΔN100, a mutant that has the N-terminal J domain deletion and that lost suppressive activity on IKK, continued to proliferate. Similar data were obtained with A375 human melanoma cells. Ad.EGFP or Ad.EGFP-hTd-1ΔN100 ex vivo-transduced A375 cells injected subcutaneously into nude mice produced growing tumors, whereas Ad.EGFP-hTid-1-transduced cells did not. Collectively, the data suggest that hTid-1 represses the activity of NF-κB through physical and functional interactions with the IKK complex and IκB and, in doing so, it modulates cell growth and death.

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