Chromatin-bound mitogen-activated protein kinases transmit dynamic signals in transcription complexes in β-cells

Abstract

MAPK pathways regulate transcription through phosphorylation of transcription factors and other DNA-binding proteins. In pancreatic ␤-cells, ERK1/2 are required for transcription of the insulin gene and several other genes in response to glucose. We show that binding of glucose-sensitive transcription activators and repressors to the insulin gene promoter depends on ERK1/2 activity. We also find that glucose and NGF stimulate the binding of ERK1/2 to the insulin gene and other promoters. An ERK1/2 cascade module, including MEK1/2 and Rsk, are found in complexes bound to these promoters. These findings imply that MAPK-containing signaling complexes are positioned on sensitive promoters with their protein substrates to modulate transcription in situ in response to incoming signals.c-fos ͉ C/EBP-␤ ͉ ERK1/2 ͉ hyperglycemia ͉ insulin gene transcription

Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription

“…Activation of these kinases by IL-1␤ resulted in their rapid association with the insulin gene promoter in human islets as assessed by chromatin immunoprecipitation (ChIP) (Fig. 2 B-D), as was previously shown for glucose-induced activation of ERK1/2, its effector kinase Rsk, and calcineurin (22). Sequential ChIP suggested that the three MAPKs and the ERK effector kinase Rsk were bound to the same DNA fragments (Fig.…”

“…Inhibition is paralleled by loss of several factors that stimulate and a gain of factors own to inhibit insulin gene transcription (20,22) (Fig. 5, models).…”

“…Glucose induces the binding of PDX-1, BETA2, MafA, and NFAT, all important for glucoseinduced insulin gene transcription, to the insulin gene promoter (14,16,20,22). C/EBP-␤ and Jun are among factors responsive to IL-1␤, which interfere with insulin gene transcription.…”

“…NFAT, which is activated by glucose and other agents that depolarize ␤ cells, also forms complexes with MafA and stimulates the insulin gene promoter in a manner dependent on its dephosphorylation by the calcium-dependent phosphatase calcineurin (19)(20)(21). The stimulatory actions of these four glucose-sensitive factors are blocked by inhibition of the ERK1/2 mitogen-activated protein kinase (MAPK) pathway (20,22). ERK1/2 activation by glucose is also dependent on calcineurin in ␤ cells (23).…”

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

“…Moreover, the fact that both ERK1/2 and PKB inhibition seem to reverse the effects of ISO stimulation on these identified genes would seem to indicate that both pathways play a role in the regulation of gene expression by nuclear βARs. This may be through MAPK or PKB modulation of the signalling proteins themselves, modulation of the transcriptional machinery or via alterations in the occupancy of chromatin sites by ERK and other protein kinases [43,44]. Further, given the already identified role of MAPKs in regulating mRNA stability [45], further experiments need to be conducted to determine if the regulation that we see is actually due to a changes in the level of de novo mRNA synthesis or reduced mRNA stability.…”