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Degradation of the inducible cAMP early repressor (ICER) by the ubiquitin-proteasome pathway.

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Affiliations

  • 1. Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
      Authors
    • Folco EJ 1
    (1 author)

The Biochemical Journal, 01 Nov 1997, 328 ( Pt 1):37-43
https://doi.org/10.1042/bj3280037 PMID: 9359831 PMCID: PMC1218884

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Abstract 

The inducible cAMP early repressor (ICER) is a powerful transcriptional inhibitor that plays an important role in the regulation of the cAMP-dependent transcriptional response in the neuroendocrine system. ICER activity is primarily determined by its intracellular concentration, rather than by post-translational modifications, such as phosphorylation. We investigated the mechanisms that regulate the levels of ICER transcript and polypeptides in cardiocytes, myogenic (C2C12) and pituitary-derived (GH3) cell lines. We show that in primary cardiocytes and GH3 cells ICER was inducible by cAMP but not by membrane depolarization. Moreover, lactacystin, a specific proteasome inhibitor, decreased the rate of ICER degradation. This effect was associated with the accumulation of ICER-ubiquitin conjugates. We conclude that the intracellular levels of ICER are controlled by the ubiquitin-proteasome pathway for protein breakdown.

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Biochem J. 1997 Nov 15; 328(Pt 1): 37–43.
PMCID: PMC1218884
PMID: 9359831

Degradation of the inducible cAMP early repressor (ICER) by the ubiquitin-proteasome pathway.

E J Folco and G Koren
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Abstract

The inducible cAMP early repressor (ICER) is a powerful transcriptional inhibitor that plays an important role in the regulation of the cAMP-dependent transcriptional response in the neuroendocrine system. ICER activity is primarily determined by its intracellular concentration, rather than by post-translational modifications, such as phosphorylation. We investigated the mechanisms that regulate the levels of ICER transcript and polypeptides in cardiocytes, myogenic (C2C12) and pituitary-derived (GH3) cell lines. We show that in primary cardiocytes and GH3 cells ICER was inducible by cAMP but not by membrane depolarization. Moreover, lactacystin, a specific proteasome inhibitor, decreased the rate of ICER degradation. This effect was associated with the accumulation of ICER-ubiquitin conjugates. We conclude that the intracellular levels of ICER are controlled by the ubiquitin-proteasome pathway for protein breakdown.

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Selected References

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  • Habener JF. Cyclic AMP response element binding proteins: a cornucopia of transcription factors. Mol Endocrinol. 1990 Aug;4(8):1087–1094. [Abstract] [Google Scholar]
  • Lalli E, Sassone-Corsi P. Signal transduction and gene regulation: the nuclear response to cAMP. J Biol Chem. 1994 Jul 1;269(26):17359–17362. [Abstract] [Google Scholar]
  • Lewis EJ, Harrington CA, Chikaraishi DM. Transcriptional regulation of the tyrosine hydroxylase gene by glucocorticoid and cyclic AMP. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3550–3554. [Europe PMC free article] [Abstract] [Google Scholar]
  • Hagiwara M, Alberts A, Brindle P, Meinkoth J, Feramisco J, Deng T, Karin M, Shenolikar S, Montminy M. Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB. Cell. 1992 Jul 10;70(1):105–113. [Abstract] [Google Scholar]
  • Wadzinski BE, Wheat WH, Jaspers S, Peruski LF, Jr, Lickteig RL, Johnson GL, Klemm DJ. Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. Mol Cell Biol. 1993 May;13(5):2822–2834. [Europe PMC free article] [Abstract] [Google Scholar]
  • Foulkes NS, Borrelli E, Sassone-Corsi P. CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell. 1991 Feb 22;64(4):739–749. [Abstract] [Google Scholar]
  • Karpinski BA, Morle GD, Huggenvik J, Uhler MD, Leiden JM. Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4820–4824. [Europe PMC free article] [Abstract] [Google Scholar]
  • Molina CA, Foulkes NS, Lalli E, Sassone-Corsi P. Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell. 1993 Dec 3;75(5):875–886. [Abstract] [Google Scholar]
  • Borrelli E, Montmayeur JP, Foulkes NS, Sassone-Corsi P. Signal transduction and gene control: the cAMP pathway. Crit Rev Oncog. 1992;3(4):321–338. [Abstract] [Google Scholar]
  • Foulkes NS, Mellström B, Benusiglio E, Sassone-Corsi P. Developmental switch of CREM function during spermatogenesis: from antagonist to activator. Nature. 1992 Jan 2;355(6355):80–84. [Abstract] [Google Scholar]
  • Stehle JH, Foulkes NS, Molina CA, Simonneaux V, Pévet P, Sassone-Corsi P. Adrenergic signals direct rhythmic expression of transcriptional repressor CREM in the pineal gland. Nature. 1993 Sep 23;365(6444):314–320. [Abstract] [Google Scholar]
  • Desdouets C, Matesic G, Molina CA, Foulkes NS, Sassone-Corsi P, Brechot C, Sobczak-Thepot J. Cell cycle regulation of cyclin A gene expression by the cyclic AMP-responsive transcription factors CREB and CREM. Mol Cell Biol. 1995 Jun;15(6):3301–3309. [Europe PMC free article] [Abstract] [Google Scholar]
  • Lalli E, Sassone-Corsi P. Thyroid-stimulating hormone (TSH)-directed induction of the CREM gene in the thyroid gland participates in the long-term desensitization of the TSH receptor. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9633–9637. [Europe PMC free article] [Abstract] [Google Scholar]
  • Monaco L, Foulkes NS, Sassone-Corsi P. Pituitary follicle-stimulating hormone (FSH) induces CREM gene expression in Sertoli cells: involvement in long-term desensitization of the FSH receptor. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10673–10677. [Europe PMC free article] [Abstract] [Google Scholar]
  • Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell. 1994 Oct 7;79(1):13–21. [Abstract] [Google Scholar]
  • Hochstrasser M, Ellison MJ, Chau V, Varshavsky A. The short-lived MAT alpha 2 transcriptional regulator is ubiquitinated in vivo. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4606–4610. [Europe PMC free article] [Abstract] [Google Scholar]
  • Kornitzer D, Raboy B, Kulka RG, Fink GR. Regulated degradation of the transcription factor Gcn4. EMBO J. 1994 Dec 15;13(24):6021–6030. [Europe PMC free article] [Abstract] [Google Scholar]
  • Treier M, Staszewski LM, Bohmann D. Ubiquitin-dependent c-Jun degradation in vivo is mediated by the delta domain. Cell. 1994 Sep 9;78(5):787–798. [Abstract] [Google Scholar]
  • Stancovski I, Gonen H, Orian A, Schwartz AL, Ciechanover A. Degradation of the proto-oncogene product c-Fos by the ubiquitin proteolytic system in vivo and in vitro: identification and characterization of the conjugating enzymes. Mol Cell Biol. 1995 Dec;15(12):7106–7116. [Europe PMC free article] [Abstract] [Google Scholar]
  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990 Dec 21;63(6):1129–1136. [Abstract] [Google Scholar]
  • Murray A. Cyclin ubiquitination: the destructive end of mitosis. Cell. 1995 Apr 21;81(2):149–152. [Abstract] [Google Scholar]
  • Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL. Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science. 1995 May 5;268(5211):726–731. [Abstract] [Google Scholar]
  • Mori Y, Matsubara H, Folco E, Siegel A, Koren G. The transcription of a mammalian voltage-gated potassium channel is regulated by cAMP in a cell-specific manner. J Biol Chem. 1993 Dec 15;268(35):26482–26493. [Abstract] [Google Scholar]
  • Sheng M, McFadden G, Greenberg ME. Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron. 1990 Apr;4(4):571–582. [Abstract] [Google Scholar]
  • Van Nguyen T, Kobierski L, Comb M, Hyman SE. The effect of depolarization on expression of the human proenkephalin gene is synergistic with cAMP and dependent upon a cAMP-inducible enhancer. J Neurosci. 1990 Aug;10(8):2825–2833. [Abstract] [Google Scholar]
  • Mori S, Tanaka K, Omura S, Saito Y. Degradation process of ligand-stimulated platelet-derived growth factor beta-receptor involves ubiquitin-proteasome proteolytic pathway. J Biol Chem. 1995 Dec 8;270(49):29447–29452. [Abstract] [Google Scholar]
  • Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994 Sep 9;78(5):761–771. [Abstract] [Google Scholar]
  • Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773–785. [Abstract] [Google Scholar]
  • Ward CL, Omura S, Kopito RR. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell. 1995 Oct 6;83(1):121–127. [Abstract] [Google Scholar]
  • Sheng M, Thompson MA, Greenberg ME. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science. 1991 Jun 7;252(5011):1427–1430. [Abstract] [Google Scholar]
  • Kim TK, Maniatis T. Regulation of interferon-gamma-activated STAT1 by the ubiquitin-proteasome pathway. Science. 1996 Sep 20;273(5282):1717–1719. [Abstract] [Google Scholar]
  • Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995 Aug 4;269(5224):682–685. [Abstract] [Google Scholar]
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