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Supplement: Nutritional Genomics and Proteomics in Cancer Prevention

ZBP-89 Mediates Butyrate Regulation of Gene Expression^{1 ,2}

Juanita L. Merchant^*,,3, Longchuan Bai^* and Morihiro Okada^*

Departments of ^* Internal Medicine and Physiology, University of Michigan, Ann Arbor, MI 48109

³ To whom correspondence should be addressed. E-mail: merchanj{at}umich.edu.

Inducible p53-independent regulation of the cyclin-dependent kinase inhibitor p21^Waf1 transcription is mediated through its proximal GC-rich sites. Prior studies have shown that Sp1, Sp3 and the histone acetyltransferase coactivator p300 are components of the complexes that bind to these sites. Although Sp1 and Sp3 collaborate with p300, a direct interaction between Sp1 and p300 does not occur. Zinc-finger binding protein-89 (ZBP-89, also known as BFCOL1, BERF-1 and ZNF-148) is a Krüppel-type zinc-finger transcription factor that binds to the same GC-rich sequences as Sp1. We sought to determine whether ZBP-89 is a target of p300 during butyrate induction of p21^Waf1. This review summarizes the evidence that supports a crucial role for ZBP-89 in butyrate regulation of p21^Waf1. Adenovirus-mediated expression of ZBP-89 in HT-29 cells reveals that ZBP-89 potentiates butyrate induction of endogenous p21^Waf1 gene expression. DNA-protein interaction assays demonstrate that Sp1, Sp3 and ZBP-89 bind the p21^Waf1 promoter at -245 to -215. Coprecipitation assays reveal that p300 preferentially binds to the N-terminus of ZBP-89. ZBP-89 also induces p21^Waf1 through stabilization of p53. Although ZBP-89 binds mutant and wild-type p53, only wild-type p53 is stabilized. Moreover, mutant p53 shifts the subnuclear location of ZBP-89 to the nuclear periphery, which is a domain rich in heterochromatin. This finding led to the conclusion that mutant p53 exerts a dominant negative effect on ZBP-89. We propose that gene silencing by mutant p53 might be mediated by sequestering ZBP-89 within heterochromatin regions at the nuclear periphery. Overall, ZBP-89 is a butyrate-regulated coactivator of p53 and is able to induce p21^Waf1 gene expression through both p53-dependent and -independent mechanisms to inhibit cell growth.

KEY WORDS: • p53 • p21^Waf1 • zinc finger • apoptosis • p300 • heterochromatin

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