Abstract
Krüppel-like factor 6 (KLF6) is a zinc finger transcription factor and tumor suppressor that is inactivated in a number of human cancers by mutation, allelic loss, and/or promoter methylation. A key mechanism of growth inhibition by wild-type KLF6 is through p53-independent up-regulation of p21(WAF1/cip1) (CDKN1A), which is abrogated in several tumor-derived mutants. Here we show by chromatin immunoprecipitation that transactivation of p21(WAF1/cip1) by KLF6 occurs through its direct recruitment to the p21(WAF1/cip1) promoter and requires acetylation by histone acetyltransferase activity of either cyclic AMP-responsive element binding protein-binding protein or p300/CBP-associated factor. Direct lysine acetylation of KLF6 peptides can be shown by mass spectrometry. A single lysine-to-arginine point mutation (K209R) derived from prostate cancer reduces acetylation of KLF6 and abrogates its capacity to up-regulate endogenous p21(WAF1/cip1) and reduce cell proliferation. These data indicate that acetylation may regulate KLF6 function, and its loss in some tumor-derived mutants could contribute to its failure to suppress growth in prostate cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylation
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Amino Acid Sequence
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Animals
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Binding Sites
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Chromatin Immunoprecipitation
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Histone Acetyltransferases / metabolism
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Histones / metabolism
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Humans
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism*
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Male
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Mice
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Molecular Sequence Data
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NIH 3T3 Cells
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Transcription Factors / metabolism
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Transcriptional Activation
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Zinc Fingers
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p300-CBP Transcription Factors
Substances
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclic AMP Response Element-Binding Protein
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Cyclin-Dependent Kinase Inhibitor p21
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Histones
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KLF6 protein, human
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors
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Proto-Oncogene Proteins
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Transcription Factors
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Histone Acetyltransferases
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p300-CBP Transcription Factors
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p300-CBP-associated factor