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  - 
TY  - JOUR
A1  - Lorenzin, Francesca
A1  - Benary, Uwe
A1  - Baluapuri, Apoorva
A1  - Walz, Susanne
A1  - Jung, Lisa Anna
A1  - von Eyss, Björn
A1  - Kisker, Caroline
A1  - Wolf, Jana
A1  - Eilers, Martin
A1  - Wolf, Elmar
T1  - Different promoter affinities account for specificity in MYC-dependent gene regulation
JF  - eLife
N2  - Enhanced expression of the MYC transcription factor is observed in the majority of tumors. Two seemingly conflicting models have been proposed for its function: one proposes that MYC enhances expression of all genes, while the other model suggests gene-specific regulation. Here, we have explored the hypothesis that specific gene expression profiles arise since promoters differ in affinity for MYC and high-affinity promoters are fully occupied by physiological levels of MYC. We determined cellular MYC levels and used RNA- and ChIP-sequencing to correlate promoter occupancy with gene expression at different concentrations of MYC. Mathematical modeling showed that binding affinities for interactions of MYC with DNA and with core promoter-bound factors, such as WDR5, are sufficient to explain promoter occupancies observed in vivo. Importantly, promoter affinity stratifies different biological processes that are regulated by MYC, explaining why tumor-specific MYC levels induce specific gene expression programs and alter defined biological properties of cells.
KW  - MYC
KW  - promoter affinity
KW  - human
KW  - mathematical modeling
KW  - mouse
KW  - ChIP-sequencing
KW  - MIZ1
KW  - cancer biology
KW  - cell biology
KW  - WDR5
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162913
VL  - 5
ER  -