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

Cinzia Brunacci, Danilo Piobbico, Daniela Bartoli, Marilena Castelli, Stefania Pieroni, Marina Maria Bellet, Mariapia Viola-Magni, Maria Agnese Della Fazia, Giuseppe Servillo

Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy.

Liver international : official journal of the International Association for the Study of the Liver 2010 Mar

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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. 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. 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. 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.

Citation

Cinzia Brunacci, Danilo Piobbico, Daniela Bartoli, Marilena Castelli, Stefania Pieroni, Marina Maria Bellet, Mariapia Viola-Magni, Maria Agnese Della Fazia, Giuseppe Servillo. Identification and characterization of a novel peptide interacting with cAMP-responsive elements binding and cAMP-responsive elements modulator in mouse liver. Liver international : official journal of the International Association for the Study of the Liver. 2010 Mar;30(3):388-95