Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway.

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-dependent 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.
Mesh Terms:
Animals, Basic Helix-Loop-Helix Transcription Factors, Calcium-Calmodulin-Dependent Protein Kinases, Cell Differentiation, Cells, Cultured, Chromatin Immunoprecipitation, DNA-Binding Proteins, Electrophoretic Mobility Shift Assay, Enzyme Activation, Gene Expression Regulation, Homeodomain Proteins, Neurons, Phosphorylation, Poly(ADP-ribose) Polymerases, Rats, Repressor Proteins, Stem Cells, Transcriptional Activation
Cell
Date: Dec. 17, 2004
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