The tumour suppressor ARF (alternative reading frame) is encoded by the INK4a (inhibitor of cyclin-dependent kinase 4)/ARF locus, which is frequently altered in human tumours. ARF binds MDM2 (murine double minute 2) and releases p53 from inhibition by MDM2, resulting in stabilization, accumulation and activation of p53. Recently, ARF has been found to associate with other proteins, but, to date, little is known about ARF-associated proteins that are implicated in post-translational regulation of ARF activity. Using a yeast two-hybrid screen, we have identified a novel protein, LZAP (LXXLL/leucine-zipper-containing ARF-binding protein), that interacts with endogenous ARF in mammalian cells. In the present study, we show that LZAP reversed the ability of ARF to inhibit HDM2's ubiquitin ligase activity towards p53, but simultaneously co-operated with ARF, maintaining p53 stability and increasing p53 transcriptional activity. Expression of LZAP, in addition to ARF, increased the percentage of cells in the G1 phase of the cell cycle. Expression of LZAP also caused activation of p53 and a p53-dependent G1 cell-cycle arrest in the absence of ARF. Taken together, our data suggest that LZAP can regulate ARF biochemical and biological activity. Additionally, LZAP has p53-dependent cell-cycle effects that are independent of ARF.
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Research Article|
December 23 2005
A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2
Jialiang Wang;
Jialiang Wang
*Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
†Departments of Otolaryngology and Cancer Biology, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, U.S.A.
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Xiaping He;
Xiaping He
‡Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
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Ying Luo;
Ying Luo
§Shanghai Genomics, Inc., 647 Song Tao Road, Building 1, Shanghai, 201203, China
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Wendell G. Yarbrough
Wendell G. Yarbrough
1
†Departments of Otolaryngology and Cancer Biology, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, U.S.A.
∥Barry Baker Laboratory for Head and Neck Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, U.S.A.
¶Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, U.S.A.
1To whom correspondence should be addressed (email wendell.yarbrough@vanderbilt.edu).
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Publisher: Portland Press Ltd
Received:
June 15 2005
Revision Received:
August 31 2005
Accepted:
September 21 2005
Accepted Manuscript online:
September 21 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 393 (2): 489–501.
Article history
Received:
June 15 2005
Revision Received:
August 31 2005
Accepted:
September 21 2005
Accepted Manuscript online:
September 21 2005
Citation
Jialiang Wang, Xiaping He, Ying Luo, Wendell G. Yarbrough; A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2. Biochem J 15 January 2006; 393 (2): 489–501. doi: https://doi.org/10.1042/BJ20050960
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