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Molecular and Cellular Biology, July 2001, p. 4670-4683, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4670-4683.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

ZBP-89 Promotes Growth Arrest through Stabilization of p53

Longchuan Bai1 and Juanita L. Merchant1,2,3,*

Departments of Internal Medicine1 and Physiology2 and Howard Hughes Medical Institute,3 University of Michigan, Ann Arbor, Michigan

Received 18 December 2000/Returned for modification 7 February 2001/Accepted 20 April 2001

Transcription factor p53 can induce growth arrest and/or apoptosis in cells through activation or repression of downstream target genes. Recently, we reported that ZBP-89 cooperates with histone acetyltransferase coactivator p300 in the regulation of p21waf1, a cyclin-dependent kinase inhibitor whose associated gene is a target gene of p53. Therefore, we examined whether ZBP-89 might also inhibit cell growth by activating p53. In the present study, we demonstrate that elevated levels of ZBP-89 induce growth arrest and apoptosis in human gastrointestinal cell lines. The ZBP-89 protein accumulated within 4 h, and the p53 protein accumulated within 16 h, of serum starvation without changes in p14ARF levels, demonstrating a physiological increase in the cellular levels of these two proteins. Overexpression of ZBP-89 stabilized the p53 protein and enhanced its transcriptional activity through direct protein-protein interactions. The DNA binding and C-terminal domains of p53 and the zinc finger domain of ZBP-89 mediated the interaction. A point mutation in the p53 DNA binding domain, R273H, greatly reduced ZBP-89-mediated stabilization but not their physical interaction. Furthermore, ZBP-89 formed a complex with p53 and MDM2 and therefore did not prevent the MDM2-p53 interaction. However, heterokaryon assays demonstrated that ZBP-89 retained p53 in the nucleus. Collectively, these data indicate that ZBP-89 regulates cell proliferation in part through its ability to directly bind the p53 protein and retard its nuclear export. Our findings further our understanding of how ZBP-89 modulates cell proliferation and reveals a novel mechanism by which the p53 protein is stabilized.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, 1150 West Medical Center Dr., MSRB I, Rm. 3510, Ann Arbor, MI 48109-0650. Phone: (734) 647-2944. Fax: (734) 936-1400. E-mail: merchanj{at}umich.edu.

Molecular and Cellular Biology, July 2001, p. 4670-4683, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4670-4683.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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