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Transcriptional regulation of the human alpha1a-adrenergic receptor gene. Characterization Of the 5'-regulatory and promoter region.

Publication ,  Journal Article
Razik, MA; Lee, K; Price, RR; Williams, MR; Ongjoco, RR; Dole, MK; Rudner, XL; Kwatra, MM; Schwinn, DA
Published in: J Biol Chem
November 7, 1997

We recently cloned cDNAs encoding three subtypes of human alpha1-adrenergic receptors (alpha1ARs), alpha1a, alpha1b, and alpha1d (Schwinn, D. A., Johnston, G. L., Page, S. O., Mosley, M. J., Wilson, K. H., Worman, N. P., Campbell, S., Fidock, M. D., Furness, L. M., Parry-Smith, D. J., Peter, B., and Bailey, D. S. (1995) J. Pharmacol. Exp. Ther. 272, 134-142) and demonstrated predominance of alpha1aARs in many human tissues (Price, D. T., Lefkowitz, R. J., Caron, M. G., Berkowitz, D., and Schwinn, D. A. (1994) Mol. Pharmacol. 45, 171-175). Several lines of evidence indicate that alpha1aARs are important in clinical diseases such as myocardial hypertrophy and benign prostatic hyperplasia. Therefore, we initiated studies to understand mechanisms underlying regulation of alpha1aAR gene transcription. A genomic clone containing 6.2 kb of 5'-untranslated region of the human alpha1aAR gene was recently isolated. Ribonuclease protection and primer extension assays indicate that alpha1aAR gene transcription occurs at multiple initiation sites with the major site located 696 base pairs upstream of the ATG, where a classic initiator sequence is located. Transfection of luciferase reporter constructs containing varying amounts of 5'-untranslated region into human SK-N-MC neuroblastoma cells indicate that a region extending 125 base pairs upstream from the main transcription initiation site contains full alpha1aAR promoter activity. Furthermore, distinct activator and suppressor elements lie 2-3 and 3-5 kilobase pairs upstream, respectively. Although the alpha1aAR promoter contains neither TATA or CAAT elements, gel shift mobility assays targeting three GC boxes immediately upstream of the main transcription initiation site confirm binding of Sp1. Activity of the alpha1aAR promoter is cell-specific, demonstrating highest activity in cells endogenously expressing alpha1aARs. The human alpha1aAR gene also contains several cis regulatory elements, including several insulin and cAMP response elements. Consistent with these observations, we provide the first evidence that treatment of SK-N-MC cells with insulin and cAMP elevating agents leads to an increase in alpha1aAR expression. In conclusion, these data represent the first characterization of the alpha1aAR gene; our findings should facilitate further studies designed to understand mechanisms regulating alpha1AR subtype-specific expression in healthy and diseased human tissue.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 7, 1997

Volume

272

Issue

45

Start / End Page

28237 / 28246

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Transcription, Genetic
  • Sp1 Transcription Factor
  • Restriction Mapping
  • Receptors, Adrenergic, alpha-1
  • Promoter Regions, Genetic
  • Molecular Sequence Data
  • Luciferases
  • Insulin
 

Citation

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Razik, M. A., Lee, K., Price, R. R., Williams, M. R., Ongjoco, R. R., Dole, M. K., … Schwinn, D. A. (1997). Transcriptional regulation of the human alpha1a-adrenergic receptor gene. Characterization Of the 5'-regulatory and promoter region. J Biol Chem, 272(45), 28237–28246. https://doi.org/10.1074/jbc.272.45.28237
Razik, M. A., K. Lee, R. R. Price, M. R. Williams, R. R. Ongjoco, M. K. Dole, X. L. Rudner, M. M. Kwatra, and D. A. Schwinn. “Transcriptional regulation of the human alpha1a-adrenergic receptor gene. Characterization Of the 5'-regulatory and promoter region.J Biol Chem 272, no. 45 (November 7, 1997): 28237–46. https://doi.org/10.1074/jbc.272.45.28237.
Razik MA, Lee K, Price RR, Williams MR, Ongjoco RR, Dole MK, et al. Transcriptional regulation of the human alpha1a-adrenergic receptor gene. Characterization Of the 5'-regulatory and promoter region. J Biol Chem. 1997 Nov 7;272(45):28237–46.
Razik, M. A., et al. “Transcriptional regulation of the human alpha1a-adrenergic receptor gene. Characterization Of the 5'-regulatory and promoter region.J Biol Chem, vol. 272, no. 45, Nov. 1997, pp. 28237–46. Pubmed, doi:10.1074/jbc.272.45.28237.
Razik MA, Lee K, Price RR, Williams MR, Ongjoco RR, Dole MK, Rudner XL, Kwatra MM, Schwinn DA. Transcriptional regulation of the human alpha1a-adrenergic receptor gene. Characterization Of the 5'-regulatory and promoter region. J Biol Chem. 1997 Nov 7;272(45):28237–28246.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 7, 1997

Volume

272

Issue

45

Start / End Page

28237 / 28246

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Transcription, Genetic
  • Sp1 Transcription Factor
  • Restriction Mapping
  • Receptors, Adrenergic, alpha-1
  • Promoter Regions, Genetic
  • Molecular Sequence Data
  • Luciferases
  • Insulin