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A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP.

Publication ,  Journal Article
Collins, S; Altschmied, J; Herbsman, O; Caron, MG; Mellon, PL; Lefkowitz, RJ
Published in: J Biol Chem
November 5, 1990

The rate of transcription of the beta 2-adrenergic receptor gene is increased in response to beta-adrenergic agonist stimulation of the receptor at the cell surface. This effect is mediated by stimulation of adenylyl cyclase and elevation of intracellular cAMP levels. We have previously shown that this responsiveness to cAMP resides in the 5'-flanking region of the human beta 2-adrenergic receptor gene (Collins, S., Bouvier, M., Bolanowski, M. A., Caron, M. G., and Lefkowitz, R. J. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 4853-4857). A 34-base pair sequence derived from the beta 2-adrenergic receptor promoter region (-70 to -37 base pairs), containing the sequence GTACGTCA, confers responsiveness to cAMP when present in either orientation 5' to the thymidine kinase promoter on the chloramphenicol acetyltransferase reporter gene. Overexpression of the catalytic subunit of protein kinase A fully substituted for forskolin in inducing expression through this sequence, indicating that the cAMP induction is mediated through this kinase. Mutations within the GTACGTCA sequence completely abolished the stimulation. A 43-kDa transcription factor (cAMP response element-binding protein) confers cAMP responsiveness through binding to specific sequences. In gel mobility shift assays, purified cAMP response element-binding protein bound to the 34-base pair oligonucleotide from the beta 2-adrenergic receptor gene with an affinity similar to that for the well-characterized cAMP response element from the human glycoprotein hormone alpha-subunit gene, and failed to bind to mutated elements. Thus, positive autoregulation of the beta 2-adrenergic receptor gene appears to occur through receptor-mediated stimulation of adenylyl cyclase, with consequent activation of cAMP response element-binding protein and stimulation of beta 2-adrenergic receptor gene transcription. These results demonstrate a novel mechanism by which a receptor (beta 2-adrenergic receptor) stimulatory for adenylyl cyclase can exert positive feedback regulation on its own expression.

Duke Scholars

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

November 5, 1990

Volume

265

Issue

31

Start / End Page

19330 / 19335

Location

United States

Related Subject Headings

  • beta-Galactosidase
  • Transfection
  • Transcription, Genetic
  • Sequence Homology, Nucleic Acid
  • Receptors, Adrenergic, beta
  • Promoter Regions, Genetic
  • Plasmids
  • Molecular Sequence Data
  • Humans
  • Genetic Vectors
 

Citation

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Collins, S., Altschmied, J., Herbsman, O., Caron, M. G., Mellon, P. L., & Lefkowitz, R. J. (1990). A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP. J Biol Chem, 265(31), 19330–19335.
Collins, S., J. Altschmied, O. Herbsman, M. G. Caron, P. L. Mellon, and R. J. Lefkowitz. “A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP.J Biol Chem 265, no. 31 (November 5, 1990): 19330–35.
Collins S, Altschmied J, Herbsman O, Caron MG, Mellon PL, Lefkowitz RJ. A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP. J Biol Chem. 1990 Nov 5;265(31):19330–5.
Collins, S., et al. “A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP.J Biol Chem, vol. 265, no. 31, Nov. 1990, pp. 19330–35.
Collins S, Altschmied J, Herbsman O, Caron MG, Mellon PL, Lefkowitz RJ. A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP. J Biol Chem. 1990 Nov 5;265(31):19330–19335.

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

November 5, 1990

Volume

265

Issue

31

Start / End Page

19330 / 19335

Location

United States

Related Subject Headings

  • beta-Galactosidase
  • Transfection
  • Transcription, Genetic
  • Sequence Homology, Nucleic Acid
  • Receptors, Adrenergic, beta
  • Promoter Regions, Genetic
  • Plasmids
  • Molecular Sequence Data
  • Humans
  • Genetic Vectors