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Miz1 Is a Critical Repressor of cdkn1a during Skin Tumorigenesis

Authors
Journal
PLoS ONE
1932-6203
Publisher
Public Library of Science
Publication Date
Volume
7
Issue
4
Identifiers
DOI: 10.1371/journal.pone.0034885
Keywords
  • Research Article
  • Biology
  • Biochemistry
  • Proteins
  • Dna-Binding Proteins
  • Regulatory Proteins
  • Immunochemistry
  • Genetics
  • Gene Expression
  • Dna Transcription
  • Molecular Genetics
  • Gene Regulation
  • Animal Genetics
  • Gene Function
  • Histology
  • Model Organisms
  • Animal Models
  • Mouse
  • Molecular Cell Biology
  • Cell Growth
  • Medicine
  • Oncology
  • Basic Cancer Research
  • Oncology Agents
Disciplines
  • Biology
  • Chemistry

Abstract

The transcription factor Miz1 forms repressive DNA-binding complexes with the Myc, Gfi-1 and Bcl-6 oncoproteins. Known target genes of these complexes encode the cyclin-dependent kinase inhibitors (CKIs) cdkn2b (p15Ink4), cdkn1a (p21Cip1), and cdkn1c (p57Kip2). Whether Miz1-mediated repression is important for control of cell proliferation in vivo and for tumor formation is unknown. Here we show that deletion of the Miz1 POZ domain, which is critical for Miz1 function, restrains the development of skin tumors in a model of chemically-induced, Ras-dependent tumorigenesis. While the stem cell compartment appears unaffected, interfollicular keratinocytes lacking functional Miz1 exhibit a reduced proliferation and an accelerated differentiation of the epidermis in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Tumorigenesis, proliferation and normal differentiation are restored in animals lacking cdkn1a, but not in those lacking cdkn2b. Our data demonstrate that Miz1-mediated attenuation of cell cycle arrest pathways via repression of cdkn1a has a critical role during tumorigenesis in the skin.

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