TY  - JOUR
A1  - Münst, Bernhard
A1  - Thier, Marc Christian
A1  - Winnemöller, Dirk
A1  - Helfen, Martina
A1  - Thummer, Rajkumar P.
A1  - Edenhofer, Frank
T1  - Nanog induces suppression of senescence through downregulation of p27\(^{KIP1}\) expression
JF  - Journal of Cell Science
N2  - A comprehensive analysis of the molecular network of cellular factors establishing and maintaining pluripotency as well as self renewal of pluripotent stem cells is key for further progress in understanding basic stem cell biology. Nanog is necessary for the natural induction of pluripotency in early mammalian development but dispensable for both its maintenance and its artificial induction. To gain further insight into the molecular activity of Nanog, we analyzed the outcomes of Nanog gain-of-function in various cell models employing a recently developed biologically active recombinant cell-permeant protein, Nanog-TAT. We found that Nanog enhances the proliferation of both NIH 3T3 and primary fibroblast cells. Nanog transduction into primary fibroblasts results in suppression of senescence-associated beta-galactosidase activity. Investigation of cell cycle factors revealed that transient activation of Nanog correlates with consistent downregulation of the cell cycle inhibitor p27\(^{KIP1}\) (also known as CDKN1B). By performing chromatin immunoprecipitation analysis, we confirmed bona fide Nanog-binding sites upstream of the p27\(^{KIP1}\) gene, establishing a direct link between physical occupancy and functional regulation. Our data demonstrates that Nanog enhances proliferation of fibroblasts through transcriptional regulation of cell cycle inhibitor p27 gene.
KW  - Embryonic stem cell
KW  - Protein transduction
KW  - Pluripotency
KW  - Senescence
KW  - Cell reprogramming
KW  - p27(KIP1)
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190761
VL  - 129
IS  - 5
ER  - 
TY  - JOUR
A1  - Scognamiglio, Roberta
A1  - Cabezas-Wallscheid, Nina
A1  - Thier, Marc Christian
A1  - Altamura, Sandro
A1  - Reyes, Alejandro
A1  - Prendergast, Áine M.
A1  - Baumgärtner, Daniel
A1  - Carnevalli, Larissa S.
A1  - Atzberger, Ann
A1  - Haas, Simon
A1  - von Paleske, Lisa
A1  - Boroviak, Thorsten
A1  - Wörsdörfer, Philipp
A1  - Essers, Marieke A. G.
A1  - Kloz, Ulrich
A1  - Eisenman, Robert N.
A1  - Edenhofer, Frank
A1  - Bertone, Paul
A1  - Huber, Wolfgang
A1  - van der Hoeven, Franciscus
A1  - Smith, Austin
A1  - Trumpp, Andreas
T1  - Myc depletion induces a pluripotent dormant state mimicking diapause
JF  - Cell
N2  - Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state.
KW  - hematopoietic stem cells
KW  - leukemia inhibitory factor
KW  - c-Myc
KW  - N-Myc
KW  - gene expression
KW  - embryonic stem cells
KW  - self-renewal
KW  - protein synthesis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190868
VL  - 164
IS  - 4
ER  -