| 9685371 | Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway. | Ju BG, etal., Cell. 2004 Dec 17;119(6):815-29. | Switching specific patterns of gene repression and activation in response to precise temporal/spatial signals is critical for normal development. Here we report a pathway in which induction of CaMKIIdelta triggers an unexpected switch in the function of the HES1 transcription factor from a TLE-depe ndent repressor to an activator required for neuronal differentiation. These events are based on activation of the poly(ADP-ribose) polymerase1 (PARP-1) sensor component of the groucho/TLE-corepressor complex mediating dismissal of the corepressor complex from HES1-regulated promoters. In parallel, CaMKIIdelta mediates a required phosphorylation of HES1 to permit neurogenic gene activation, revealing the ability of a specific signaling pathway to modulate both the derepression and the subsequent coactivator recruitment events required for transcriptional activation of a neurogenic program. The identification of PARP-1 as a regulated promoter-specific exchange factor required for activation of specific neurogenic gene programs is likely to be prototypic of similar molecular mechanisms. | 15607978 | 2004-01-01 |
| 11085384 | Grg3/TLE3 and Grg1/TLE1 induce monohormonal pancreatic beta-cells while repressing alpha-cell functions. | Metzger DE, etal., Diabetes. 2014 May;63(5):1804-16. doi: 10.2337/db13-0867. Epub 2014 Jan 31. | In the pancreas, alpha- and beta-cells possess a degree of plasticity. In vitro differentiation of pluripotent cells yields mostly alpha- and polyhormonal beta-like cells, indicating a gap in understanding of how functional monohormonal beta-cells are formed and of the endogenous repressive mechanis ms used to maintain beta-cell identity. We show that the corepressor Grg3 is expressed in almost all beta-cells throughout embryogenesis to adulthood. However, Grg3 is expressed in fewer nascent alpha-cells and is progressively lost from alpha-cells as endocrine cells mature into adulthood. We show that mouse Grg3(+/-) beta-cells have increased alpha-specific gene expression, and Grg3(+/-) pancreata have more alpha-cells and more polyhormonal cells, indicating that Grg3 is required for the physiologic maintenance of monohormonal beta-cell identity. Ectopic expression of Grg3 in alpha-cells represses glucagon and Arx, and the addition of Pdx1 induces Glut2 expression and glucose-responsive insulin secretion. Furthermore, we found that Grg1 is the predominant Groucho expressed in human beta-cells but acts functionally similarly to Grg3. Overall, we find that Grg3 and Grg1 establish a monohormonal beta-cell identity, and Groucho family members may be useful tools or markers for making functional beta-cells. | 24487024 | 2014-06-01 |
| 8553567 | Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif. | Grbavec D and Stifani S, Biochem Biophys Res Commun. 1996 Jun 25;223(3):701-5. | Groucho is a protein implicated in Notch signaling and involved in segmentation and neural development in Drosophila. Groucho forms transcription complexes with the basic helix-loop-helix proteins encoded by the hairy/Enhancer of split ("hairy-like") gene family. These interactions are mediated by the carboxyl-terminal WRPW motif of Hairy-like proteins. We are interested in determining whether Groucho and its mammalian homologues, the TLE proteins, perform conserved functions. We show that TLE1 interacts with HES-1, a murine homologue of Drosophila Hairy-like proteins, both in the yeast two-hybrid assay and in an interaction assay based on glutathione S-transferase fusion proteins. These results show that Groucho/TLE proteins and Hairy-like/HES proteins are involved in similar interactions in Drosophila and mammals and further suggest that these proteins perform conserved cellular functions. | 8687460 | 1996-05-01 |
| 11521368 | Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-kappaB inflammatory pathway. | Ramasamy S, etal., Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):1871-6. doi: 10.1073/pnas.1511380113. Epub 2016 Feb 1. | Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1 an>-deficient (Tle1(Delta/Delta)) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1(Delta/Delta) mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1(Delta/Delta) macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1(Delta/Delta) mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-kappaB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1(Delta/Delta) mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression. | 26831087 | 2016-08-01 |
