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Molecular and Cellular Biology, January 2005, p. 44-59, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.44-59.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Hua Cheng,¹ Carlo Cenciarelli,² Gina Nelkin,¹ Rachel Tsan,¹ Dominic Fan,¹ Cecilia Cheng-Mayer,³ and Isaiah J. Fidler^1*

Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas,¹ Università Cattolica del Sacro Cuore, Istituto di Neurochirurgia, Rome, Italy,² Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York³

Received 26 March 2004/ Returned for modification 3 May 2004/ Accepted 30 September 2004

hTid-1, a human homolog of the Drosophila tumor suppressor l(2)Tid and a novel DnaJ protein, regulates the activity of nuclear factor B (NF-B), but its mechanism is not established. We report here that hTid-1 strongly associated with the cytoplasmic protein complex of NF-B-IB through direct interaction with IB/ß and the IKK/ß subunits of the IB 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 IB. 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-1N100, 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-1N100 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-B through physical and functional interactions with the IKK complex and IB and, in doing so, it modulates cell growth and death.

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* Corresponding author. Mailing address: Department of Cancer Biology, Unit 173, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-8580. Fax: (713) 792-8747. E-mail: ifidler{at}mdanderson.org.

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Molecular and Cellular Biology, January 2005, p. 44-59, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.44-59.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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