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Miz1 Is a Critical Repressor of cdkn1a during Skin Tumorigenesis

Please always quote using this URN: urn:nbn:de:bvb:20-opus-133285
  • 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 ofThe 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.show moreshow less

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Metadaten
Author: Jan Hönnemann, Adrian Sanz-Moreno, Elmar Wolf, Martin Eilers, Hans-Peter Elsässer
URN:urn:nbn:de:bvb:20-opus-133285
Document Type:Journal article
Faculties:Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften
Language:English
Parent Title (English):PLoS One
Year of Completion:2012
Volume:7
Issue:4
Pagenumber:e34885
Source:PLoS ONE 7(4): e34885. doi:10.1371/journal.pone.0034885
DOI:https://doi.org/10.1371/journal.pone.0034885
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:P15(INK4B); P21; POZ domain; c-myc; cancer cells; cell-cycle arrest; differentiation; senescence; transcription factor MIZ-1; tumor suppressor
Release Date:2017/01/13
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung