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J. Biol. Chem., Vol. 279, Issue 43, 44563-44572, October 22, 2004

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Tax Deregulation of NF-B2 p100 Processing Involves Both -TrCP-dependent and -independent Mechanisms^*

Zhaoxia Qu, Guoliang Qing, Arnold Rabson, and Gutian Xiao¶

From the Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, and Center for Advanced Biotechnology and Medicine (CABM), and Cancer Institute of New Jersey, Department of Molecular Genetics, Microbiology and Immunology, The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08855

Processing of the nf-b2 gene product p100 to generate p52 is a tightly regulated event, consistent with the fact that the processing product, p52, is hardly detected in most cell types, including T cells, although the precursor p100 is expressed abundantly in these cells. However, in T cells transformed by the human T-cell leukemia virus type I (HTLV-I), p100 processing is very active, resulting in high level expression of p52. Because overproduction of p52 is associated with lymphoid hyperplasia and transformation, deregulation of p100 processing may be part of the oncogenic mechanism of HTLV-I. We demonstrated previously that HTLV-I Tax oncoprotein is a potent inducer of p100 processing through specific targeting of IKK via IKK to p100 to trigger p100 phosphorylation and ubiquitination. In this study, we further show that Tax-mediated recruitment of IKK to p100 requires serines 866 and 870 of p100, shown to be essential for inducible processing of p100. Upon interaction with p100, activated IKK phosphorylates both N- and C-terminal serines of p100 (serines 99, 108, 115, 123 and 872), serving as a critical step in Tax-induced p100 processing. Using a genetic approach, we find that -transducin repeat-containing protein, a component of the SCF ubiquitin ligase complex, previously shown to be required for physiological p100 processing mediated by nuclear factor-B-inducing kinase, is only partially involved in Tax-induced processing of p100. These results indicate that both -transducin repeat-containing protein-dependent and -independent mechanisms contribute to Tax-deregulated p100 processing, further suggesting the involvement of different mechanisms in cellular and viral pathways of p100 processing.

Received for publication, April 2, 2004 , and in revised form, July 1, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Nelson Biological Laboratories, Rutgers, The State University of New Jersey, 604 Allison Rd., Piscataway, NJ 08854. Tel.: 732-445-2839; Fax: 732-445-5870; E-mail: xiao{at}biology.rutgers.edu.

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