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MBC in Press, published online ahead of print November 3, 2004
Mol. Biol. Cell 10.1091/mbc.E04-04-0339

A more recent version of this article appeared on January 1, 2005
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Submitted on April 26, 2004
Revised on October 8, 2004
Accepted on October 26, 2004

Gap Junctions Regulate Extracellular Signal-regulated Kinase (ERK) Signaling to Affect Gene Transcription

Joseph P. Stains* and Roberto Civitelli{dagger}

Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110

Monitoring Editor: Carl-Henrik Heldin

Osteoblasts are highly coupled by gap junctions formed by connexin43. Overexpression of connexin45 in osteoblasts results in decreased chemical and electrical coupling and reduces gene transcription from connexin response elements (CxREs) in the osteocalcin and collagen I{alpha}1 promoters. Here, we demonstrate that transcription from the gap junction-dependent osteocalcin CxRE is regulated by extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) cascades. Overexpression of a constitutively active MEK, Raf, or Ras can increase transcription more than twofold of the CxRE; while inhibition of MEK or PI3K can decrease transcription threefold from the osteocalcin CxRE. Importantly, disruption of gap junctional communication by overexpression of connexin45 or treatment with pharmacological inhibitors of gap junctions results in reduced Raf, ERK, and Akt activation. The consequence of attenuated gap junction-dependent signal cascade activation is a decrease in Sp1 phosphorylation by ERK, resulting in decreased Sp1 recruitment to the CxRE and inhibited gene transcription. These data establish that ERK/PI3K signaling is required for the optimal elaboration of transcription from the osteocalcin CxRE, and that disruption of gap junctional communication attenuates the ability of cells to respond to an extracellular cue, presumably by limiting the propagation of second messengers among adjacent cells by connexin43-gap junctions.

*Present address: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201.

{dagger}Corresponding author. E-mail: rcivitel{at}im.wustl.edu






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