title: Critical role for lysine 685 in gene expression mediated by transcription factor unphosphorylated STAT3.
abstract: STAT3 is a pleiotropic transcription factor that is activated by the phosphorylation of tyrosine 705 in response to many cytokines and growth factors. STAT3 without Tyr-705 phosphorylation (U-STAT3) is also a potent transcription factor, and its concentration in cells increases greatly in response to STAT3 activation because the STAT3 gene can be driven by phosphorylated STAT3 dimers. We have now searched for post-translational modifications of U-STAT3 that might have a critical role in its function. An analysis by mass spectroscopy indicated that U-STAT3 is acetylated on Lys-685, and the integrity of Lys-685 is required for the expression of most U-STAT3-dependent genes. In contrast, we found only a very minor role for Lys-685 in gene expression induced in response to tyrosine-phosphorylated STAT3. U-STAT3 plays an important role in angiotensin II-induced gene expression and in the consequent development of cardiac hypertrophy and dysfunction. Mutation of Lys-685 inhibits this function of STAT3, providing new information on the role of U-STAT3 in augmenting the development of heart failure.
authors.affiliation: Departments of Molecular Genetics and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Maupali
authors.initials: M
authors.lastname: Dasgupta
authors.affiliation: Departments of Molecular Cardiology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Hamiyet
authors.initials: H
authors.lastname: Unal
authors.affiliation: Mass Spectrometry Laboratory for Protein Sequencing, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195 and.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: Departments of Molecular Genetics and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195; School of Life Science, Lanzhou University, Lanzhou, Gansu 73000, China.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
authors.affiliation: Departments of Molecular Cardiology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Sadashiva S
authors.initials: SS
authors.lastname: Karnik
authors.affiliation: Departments of Molecular Genetics and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195. Electronic address: starkg@ccf.org.
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
mesh_terms: D000107:Acetylation; D000804:Angiotensin II / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D008239:Lysine / Q000235:genetics*; D020125:Mutation, Missense; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000804:Angiotensin II; D008239:Lysine
keywords: Angiotensin II; Gene Expression; Microarray; Post-translational Modification (PTM); STAT3; U-STAT3