title: Miz1 is a critical repressor of cdkn1a during skin tumorigenesis.
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 (p15(Ink4)), cdkn1a (p21(Cip1)), and cdkn1c (p57(Kip2)). 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.
authors.affiliation: Department of Cytobiology, Philipps-University Marburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Hönnemann
authors.forename: Adrián
authors.initials: A
authors.lastname: Sanz-Moreno
authors.forename: Elmar
authors.initials: E
authors.lastname: Wolf
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Elsässer
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases
chemical_list: C493957:Cdkn1a protein, mouse; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D015127:9,10-Dimethyl-1,2-benzanthracene; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D013755:Tetradecanoylphorbol Acetate