TY  - JOUR
A1  - Timofeev, Oleg
A1  - Schlereth, Katharina
A1  - Wanzel, Michael
A1  - Braun, Attila
A1  - Nieswandt, Bernhard
A1  - Pagenstecher, Axel
A1  - Rosenwald, Andreas
A1  - Elsässer, Hans-Peter
A1  - Stiewe, Thorsten
T1  - p53 DNA Binding Cooperativity Is Essential for Apoptosis and Tumor Suppression In Vivo
JF  - Cell Reports
N2  - Four molecules of the tumor suppressor p53 assemble to cooperatively bind proapoptotic target genes. The structural basis for cooperativity consists of interactions between adjacent DNA binding domains. Mutations at the interaction interface that compromise cooperativity were identified in cancer patients, suggesting a requirement of cooperativity for tumor suppression. We report on an analysis of cooperativity mutant p53(E177R) mice. Apoptotic functions of p53 triggered by DNA damage and oncogenes were abolished in these mice, whereas functions in cell-cycle control, senescence, metabolism, and antioxidant defense were retained and were sufficient to suppress development of spontaneous T cell lymphoma. Cooperativity mutant mice are nevertheless highly cancer prone and susceptible to different oncogene-induced tumors. Our data underscore the relevance of DNA binding cooperativity for p53-dependent apoptosis and tumor suppression and highlight cooperativity mutations as a class of p53 mutations that result in a selective loss of apoptotic functions due to an altered quaternary structure of the p53 tetramer.
KW  - mutant p53
KW  - senescence
KW  - mice
KW  - tumorigenesis
KW  - restoration
KW  - damage responses
KW  - antioxidant function
KW  - p53-inducible regulator
KW  - p53-dependent apoptosis
KW  - cell-cycle arrest
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122168
VL  - 3
ER  - 
TY  - JOUR
A1  - Hönnemann, Jan
A1  - Sanz-Moreno, Adrian
A1  - Wolf, Elmar
A1  - Eilers, Martin
A1  - Elsässer, Hans-Peter
T1  - Miz1 Is a Critical Repressor of cdkn1a during Skin Tumorigenesis
JF  - PLoS One
N2  - 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.
KW  - transcription factor MIZ-1
KW  - cell-cycle arrest
KW  - c-myc
KW  - tumor suppressor
KW  - cancer cells
KW  - POZ domain
KW  - P21
KW  - differentiation
KW  - P15(INK4B)
KW  - senescence
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133285
VL  - 7
IS  - 4
ER  - 
TY  - JOUR
A1  - Sanz-Moreno, Adrian
A1  - Fuhrmann, David
A1  - Wolf, Elmar
A1  - von Eyss, Björn
A1  - Eilers, Martin
A1  - Elsässer, Hans-Peter
T1  - Miz1 Deficiency in the Mammary Gland Causes a Lactation Defect by Attenuated Stat5 Expression and Phosphorylation
JF  - PLOS ONE
N2  - Miz1 is a zinc finger transcription factor with an N-terminal POZ domain. Complexes with Myc, Bcl-6 or Gfi-1 repress expression of genes like Cdkn2b (p15(Ink4)) or Cd-kn1a (p21(Cip1)). The role of Miz1 in normal mammary gland development has not been addressed so far. Conditional knockout of the Miz1 POZ domain in luminal cells during pregnancy caused a lactation defect with a transient reduction of glandular tissue, reduced proliferation and attenuated differentiation. This was recapitulated in vitro using mouse mammary gland derived HC11 cells. Further analysis revealed decreased Stat5 activity in Miz1 Delta POZ mammary glands and an attenuated expression of Stat5 targets. Gene expression of the Prolactin receptor (PrlR) and ErbB4, both critical for Stat5 phosphorylation (pStat5) or pStat5 nuclear translocation, was decreased in Miz1 Delta POZ females. Microarray, ChIP-Seq and gene set enrichment analysis revealed a down-regulation of Miz1 target genes being involved in vesicular transport processes. Our data suggest that deranged intracellular transport and localization of PrlR and ErbB4 disrupt the Stat5 signalling pathway in mutant glands and cause the observed lactation phenotype.
KW  - C-MYC
KW  - transcription factor MIZ-1
KW  - breast-cancer cells
KW  - gene expression
KW  - epithelial cells
KW  - prolactin
KW  - transgenic mice
KW  - growth
KW  - differentiation
KW  - proliferation
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117286
VL  - 9
IS  - 2
ER  -