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ING1 Represses Transcription by Direct DNA Binding and through Effects on p53¹

Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, T2N 4N1 Canada [H. K., P. B., D. V., X. F., Y. H., K. R.]; Molecular Neurobiology [Y. M.] and Department of Internal Medicine and Bioregulation [T. J.], Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601 Japan; Department of Biochemistry Hokkaido University Graduate School of Medicine, Sapporo, 060-8638 Japan [H. N.]; Ontario Cancer Institute, Toronto, Ontario, M5G 2M9 Canada [H. V.]; and National Cancer Institute, NIH, Bethesda, Maryland 20892 [C. C. H.]

The ING family of proteins is involved in the regulation of diverse processes ranging from cell cycle and cellular senescence to apoptosis. These effects are most likely through activation of acetylation-dependent pathways that ultimately alter gene expression. Despite reports linking ING to p53 activation, the molecular basis of how ING activates p53 function has not been elucidated. In this study, we found that a subset of ING family members strongly repressed human -fetoprotein (AFP) promoter activity but stimulated the p21^WAF1 promoter in parallel experiments in the same cell type, similar to the effects of p53. The p47^ING1a isoform also repressed AFP promoter activity, but in contrast to other ING isoforms, it repressed the p21^WAF1 promoter. p47^ING3 up-regulated p21^WAF1 promoter activity, but it did not have any effect on the AFP promoter. ING1b and ING2 also repressed the AFP promoter in Hep3B p53-null cell lines, and p53 coexpression enhanced this transcriptional repression. Suppression of AFP gene transcription by ING was strongly dependent on AT-motifs that bind to the hepatocyte nuclear factor 1 (HNF1) transcription factor. Indeed, electrophoretic mobility shift assays confirmed that HNF1 binds to AT-motifs, but we found, surprisingly, that the ING1 complexes binding to these AT-motifs were devoid of HNF1 protein. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. In addition, we found that p33^ING1b physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys³⁷³ and/or Lys³⁸². These findings provide novel evidence that p33^ING1b represses AFP transcription by at least two mechanisms, one of which includes p53. The first is by binding to the AT-motif and excluding HNF1 binding while possibly targeting HAT activity to promoter regions, and the second is by increasing the levels of active, acetylated p53 via binding and inhibiting the ability of hSIR2 to deacetylate p53 protein.

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