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Molecular and Cellular Biology, April 2005, p. 3348-3356, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.3348-3356.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Posttranscriptional Downregulation of c-IAP2 by the Ubiquitin Protein Ligase c-IAP1 In Vivo

Dietrich B. Conze,1,{dagger} Lori Albert,2,{dagger},{ddagger} David A. Ferrick,3 David V. Goeddel,4 Wen-Chen Yeh,2 Tak Mak,2 and Jonathan D. Ashwell1*

Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,1 Division of Cellular and Molecular Biology, Advanced Medical Discovery Institute, Princess Margaret Hospital, Toronto, Ontario, Canada,2 Sagres Discovery, Davis,3 Tularik Inc., South San Francisco, California4

Received 27 October 2004/ Returned for modification 27 December 2004/ Accepted 21 January 2005

Inhibitor of apoptosis proteins (IAPs) c-IAP1 and c-IAP2 were identified as part of the tumor necrosis factor receptor 2 (TNFR2) signaling complex and have been implicated as intermediaries in tumor necrosis factor alpha signaling. Like all RING domain-containing IAPs, c-IAP1 and c-IAP2 have ubiquitin protein ligase (E3) activity. To explore the function of c-IAP1 in a physiologic setting, c-IAP1-deficient mice were generated by homologous gene recombination. These animals are viable and have no obvious sensitization to proapoptotic stimuli. Cells from c-IAP1–/– mice do, however, express markedly elevated levels of c-IAP2 protein in the absence of increased c-IAP2 mRNA. In contrast to reports implicating c-IAPs in the activation of NF-{kappa}B, resting and cytokine-induced NF-{kappa}B activation was not impaired in c-IAP1-deficient cells. Transient transfection studies with wild-type and E3-defective c-IAP1 revealed that c-IAP2 is a direct target for c-IAP1-mediated ubiquitination and subsequent degradation, which are potentiated by the adaptor function of TRAF2. Thus, the c-IAPs represent a pair of TNFR-associated ubiquitin protein ligases in which one regulates the expression of the other by a posttranscriptional and E3-dependent mechanism.

* Corresponding author. Mailing address: National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 37, Room 3002, Bethesda, MD 20892. Phone: (301) 496-4931. Fax: (301) 402-4844. E-mail: jda{at}pop.nci.nih.gov.

{dagger} D.B.C. and L.A. contributed equally to the present work.

{ddagger} Present address: Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8.

Molecular and Cellular Biology, April 2005, p. 3348-3356, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.3348-3356.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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