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

Michael C. Lawrence, Chunli Shao, Kathleen McGlynn, Bashoo Naziruddin, Marlon F. Levy, Melanie H. Cobb

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

During the onset of diabetes, pancreatic β cells become unable to produce sufficient insulin to maintain blood glucose within the normal range. Proinflammatory cytokines have been implicated in impaired β cell function. To understand more about the molecular events that reduce insulin gene transcription, we examined the effects of hyperglycemia alone and together with the proinflammatory cytokine interleukin-1β (IL-1β) on signal transduction pathways that regulate insulin gene transcription. Exposure to IL-1β in fasting glucose activated multiple protein kinases that associate with the insulin gene promoter and transiently increased insulin gene transcription in β cells. In contrast, cells exposed to hyperglycemic conditions were sensitized to the inhibitory actions of IL-1β. Under these conditions, IL-1β caused the association of the same protein kinases, but a different combination of transcription factors with the insulin gene promoter and began to reduce transcription within 2 h; stimulatory factors were lost, RNA polymerase II was lost, and inhibitory factors were bound to the promoter in a kinase-dependent manner.

Original languageEnglish (US)
Pages (from-to)22181-22186
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number52
DOIs
StatePublished - Dec 19 2009

Fingerprint

Protein Kinases
Chromatin
Insulin
Interleukin-1
Genes
Cytokines
RNA Polymerase II
Hyperglycemia
Blood Glucose
Fasting
Signal Transduction
Reference Values
Transcription Factors
Phosphotransferases
Glucose

Keywords

  • ERK1/2
  • Histone acetylation
  • Interleukin 1-β

ASJC Scopus subject areas

  • General

Cite this

Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription. / Lawrence, Michael C.; Shao, Chunli; McGlynn, Kathleen; Naziruddin, Bashoo; Levy, Marlon F.; Cobb, Melanie H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 52, 19.12.2009, p. 22181-22186.

Research output: Contribution to journalArticle

Lawrence, Michael C. ; Shao, Chunli ; McGlynn, Kathleen ; Naziruddin, Bashoo ; Levy, Marlon F. ; Cobb, Melanie H. / Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 52. pp. 22181-22186.
@article{09427dfd655f4071a628d66b6254c531,
title = "Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription",
abstract = "During the onset of diabetes, pancreatic β cells become unable to produce sufficient insulin to maintain blood glucose within the normal range. Proinflammatory cytokines have been implicated in impaired β cell function. To understand more about the molecular events that reduce insulin gene transcription, we examined the effects of hyperglycemia alone and together with the proinflammatory cytokine interleukin-1β (IL-1β) on signal transduction pathways that regulate insulin gene transcription. Exposure to IL-1β in fasting glucose activated multiple protein kinases that associate with the insulin gene promoter and transiently increased insulin gene transcription in β cells. In contrast, cells exposed to hyperglycemic conditions were sensitized to the inhibitory actions of IL-1β. Under these conditions, IL-1β caused the association of the same protein kinases, but a different combination of transcription factors with the insulin gene promoter and began to reduce transcription within 2 h; stimulatory factors were lost, RNA polymerase II was lost, and inhibitory factors were bound to the promoter in a kinase-dependent manner.",
keywords = "ERK1/2, Histone acetylation, Interleukin 1-β",
author = "Lawrence, {Michael C.} and Chunli Shao and Kathleen McGlynn and Bashoo Naziruddin and Levy, {Marlon F.} and Cobb, {Melanie H.}",
year = "2009",
month = "12",
day = "19",
doi = "10.1073/pnas.0912596106",
language = "English (US)",
volume = "106",
pages = "22181--22186",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "52",

}

TY - JOUR

T1 - Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription

AU - Lawrence, Michael C.

AU - Shao, Chunli

AU - McGlynn, Kathleen

AU - Naziruddin, Bashoo

AU - Levy, Marlon F.

AU - Cobb, Melanie H.

PY - 2009/12/19

Y1 - 2009/12/19

N2 - During the onset of diabetes, pancreatic β cells become unable to produce sufficient insulin to maintain blood glucose within the normal range. Proinflammatory cytokines have been implicated in impaired β cell function. To understand more about the molecular events that reduce insulin gene transcription, we examined the effects of hyperglycemia alone and together with the proinflammatory cytokine interleukin-1β (IL-1β) on signal transduction pathways that regulate insulin gene transcription. Exposure to IL-1β in fasting glucose activated multiple protein kinases that associate with the insulin gene promoter and transiently increased insulin gene transcription in β cells. In contrast, cells exposed to hyperglycemic conditions were sensitized to the inhibitory actions of IL-1β. Under these conditions, IL-1β caused the association of the same protein kinases, but a different combination of transcription factors with the insulin gene promoter and began to reduce transcription within 2 h; stimulatory factors were lost, RNA polymerase II was lost, and inhibitory factors were bound to the promoter in a kinase-dependent manner.

AB - During the onset of diabetes, pancreatic β cells become unable to produce sufficient insulin to maintain blood glucose within the normal range. Proinflammatory cytokines have been implicated in impaired β cell function. To understand more about the molecular events that reduce insulin gene transcription, we examined the effects of hyperglycemia alone and together with the proinflammatory cytokine interleukin-1β (IL-1β) on signal transduction pathways that regulate insulin gene transcription. Exposure to IL-1β in fasting glucose activated multiple protein kinases that associate with the insulin gene promoter and transiently increased insulin gene transcription in β cells. In contrast, cells exposed to hyperglycemic conditions were sensitized to the inhibitory actions of IL-1β. Under these conditions, IL-1β caused the association of the same protein kinases, but a different combination of transcription factors with the insulin gene promoter and began to reduce transcription within 2 h; stimulatory factors were lost, RNA polymerase II was lost, and inhibitory factors were bound to the promoter in a kinase-dependent manner.

KW - ERK1/2

KW - Histone acetylation

KW - Interleukin 1-β

UR - http://www.scopus.com/inward/record.url?scp=76049126005&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76049126005&partnerID=8YFLogxK

U2 - 10.1073/pnas.0912596106

DO - 10.1073/pnas.0912596106

M3 - Article

VL - 106

SP - 22181

EP - 22186

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 52

ER -