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Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. Interactions between bacterial products (MAMPs) and Toll-like receptors (TLRs) are known to be mandatory for IEC homeostasis, but how TLRs may time homeostatic functions with circadian changes is unknown. Our functional and molecular dissections of the IEC circadian...
Most studies on TCF7L2 SNP variants in the pathogenesis of type 2 diabetes (T2D) focus on a role of the encoded transcription factor TCF4 in β cells. Here, a mouse genetics approach shows that removal of TCF4 from β cells does not affect their function, whereas manipulating TCF4 levels in the liver has major effects on metabolism. In Tcf7l2 −/− mice, the immediate postnatal surge in liver...
The glucocorticoid (GC) receptor (GR), when liganded to GC, activates transcription through direct binding to simple (+)GRE DNA binding sequences (DBS). GC-induced direct repression via GR binding to complex “negative” GREs (nGREs) has been reported. However, GR-mediated transrepression was generally ascribed to indirect “tethered” interaction with other DNA-bound factors. We report that GC-induces...
Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor α (ERα) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERα in differentiated osteoclasts (ERα ΔOc/ΔOc ) and found that ERα ΔOc/ΔOc females, but not males,...
Myeloproliferative syndromes (MPS) are a heterogeneous subclass of nonlymphoid hematopoietic neoplasms which are considered to be intrinsic to hematopoietic cells. The causes of MPS are largely unknown. Here, we demonstrate that mice deficient for retinoic acid receptor γ (RARγ), develop MPS induced solely by the RARγ-deficient microenvironment. RARγ −/− mice had significantly increased granulocyte/macrophage...
We have explored the effects of two members of the p160 coregulator family on energy homeostasis. TIF2-/- mice are protected against obesity and display enhanced adaptive thermogenesis, whereas SRC-1-/- mice are prone to obesity due to reduced energy expenditure. In white adipose tissue, lack of TIF2 decreases PPARγ activity and reduces fat accumulation, whereas in brown adipose tissue it facilitates...
The activity of the N-terminal activation function AF-1 of RARα1 is abrogated upon mutation of a phosphorylatable serine residue (Ser77). Recombinant RARα was phosphorylated by a variety of proline-directed protein kinases in vitro. However, only the coexpression of cdk7 stimulated Ser77 phosphorylation in vivo and enhanced transactivation by RARα, but not by a S77A RAR mutant. Both free CAK (cdk7,...
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