Abstract
The c-Myc transcription factor regulates expression of genes related to cell growth, division, and apoptosis. Mxi1, a member of the Mad family, represses transcription of c-Myc-regulated genes by mediating chromatin condensation via histone deacetylase and the Sin3 corepressor. Mxi1 is a c-Myc antagonist and suppresses cell proliferation in vitro. Here, we describe the identification of Mxi1-0, a novel Mxi1 isoform that is alternatively transcribed from an upstream exon. Mxi1-0 and Mxi1 have different amino-terminal sequences, but share identical Max- and DNA-binding domains. Both isoforms are able to bind Max, to recognize E-box binding sites, and to interact with Sin3. Despite these similarities and in contrast to Mxi1, Mxi1-0 is predominantly localized to the cytoplasm and fails to repress c-Myc-dependent transcription. Although Mxi1-0 and Mxi1 are coexpressed in both human and mouse cells, the relative levels of Mxi1-0 are higher in primary glioblastoma tumors than in normal brain tissue. This variation in the levels of Mxi1-0 and Mxi1 suggests that Mxi1-0 may modulate the Myc-inhibitory activity of Mxi1. The identification of Mxi1-0 as an alternatively transcribed Mxi1 isoform has significant implications for the interpretation of previous Mxi1 studies, particularly those related to the phenotype of the mxi1 knockout mouse.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic Helix-Loop-Helix Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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COS Cells
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Chlorocebus aethiops
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Chromosomes, Human, Pair 10 / genetics
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Cytoplasm / chemistry
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DNA-Binding Proteins / analysis
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Exons / genetics
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Gene Expression Regulation, Neoplastic*
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Glioblastoma / genetics
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Glioblastoma / metabolism*
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Humans
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Mice
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Molecular Sequence Data
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Neuroblastoma / genetics
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Neuroblastoma / metabolism*
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Promoter Regions, Genetic
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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RNA, Messenger / analysis
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RNA, Messenger / metabolism
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Transcription Factors / analysis
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcription, Genetic
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Tumor Suppressor Proteins
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Up-Regulation
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic Helix-Loop-Helix Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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MAX protein, human
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MXI1 protein, human
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Mxi1 protein, mouse
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Myc associated factor X
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Protein Isoforms
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RNA, Messenger
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Transcription Factors
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Tumor Suppressor Proteins
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Max protein, mouse