Identification and characterization of a novel peptide interacting with cAMP-responsive elements binding and cAMP-responsive elements modulator in mouse liver

Authors

  • Cinzia Brunacci,

    1. Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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    • *Contributed equally to this paper.

  • Danilo Piobbico,

    1. Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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    • *Contributed equally to this paper.

  • Daniela Bartoli,

    1. Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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  • Marilena Castelli,

    1. Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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  • Stefania Pieroni,

    1. Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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  • Marina Maria Bellet,

    1. Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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  • Mariapia Viola-Magni,

    1. Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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  • Maria Agnese Della Fazia,

    1. Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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    • Share senior authorship of this paper.

  • Giuseppe Servillo

    1. Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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Correspondence
Giuseppe Servillo, Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Via E. dal Pozzo, 06122 Perugia, Italy
Tel: +39 0755855840
Fax: +39 0755855859
e-mail: labiomol@unipg.it

Abstract

Background/Aims: Transcription factors coupled to cyclic adenosine mono phosphate (cAMP) signalling in the cAMP-responsive elements binding (CREB)/ATF family constitute a family of activators or repressors that bind to cAMP-responsive promoter elements (CREs) in the regulatory regions of cAMP-inducible genes. A role for CREB/ATF family has been advocated in the control of hepatocellular carcinoma progression. CREB appears to be activated by the X protein of hepatitis B virus, which links to the unphosphorylated form of CREB and activates transcription, thus obviating an otherwise indispensable Ser-133 phosphorylation. Identification of factors capable of triggering transcription via cAMP-responsive elements modulator (CREM)/CREB signalling in the absence of Ser phosphorylation will improve our knowledge of the molecular mechanism of liver cell proliferation.

Methods: To isolate and study proteins binding and activating CREB and/or CREM in the liver, we performed the screening of a mouse liver cDNA library using the Two-Hybrid System.

Results: We report the identification and characterization of a novel peptide, VTIP-peptide (VTIP-P), which binds and enhances the activation of CREM/CREB, obviating the need for transcription factor phosphorylation. We demonstrated that VTIP-P physically interacts with the activation domain (AD) of the transcription factors CREB/CREM and activates transcription by modifying their phosphorylation pattern in hepatoma cells. The data allowed the conclusion that VTIP-P binds the AD of CREB and CREM by stabilizing their phosphorylation.

Conclusion: The characterization of molecules capable of interfering in the liver with an important pathway such as CREB could be significant in designing and/or developing new therapeutic approaches to the control of liver cell proliferation.

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