title: Cardiac transcription factor Nkx2.5 interacts with p53 and modulates its activity.
abstract: Transcription factor Nkx2.5, essential for heart development, regulates cardiomyocyte-specific gene expression through combinatorial interactions with other cardiac-restricted (GATA4 and dHAND) or ubiquitous (p300) transcription regulators. Here we demonstrate that Nkx2.5 and p53 synergistically activate the promoter of the striated muscle stress responsive transcriptional cofactor Ankrd2, involved in coordination of proliferation and apoptosis during myogenic differentiation. Moreover, the p53 protein is able to interact with both wild type Nkx2.5 and its mutant ΔNkx2.5 (aa 1-198) found in patients with diverse cardiac malformations. Nkx2.5 interaction site of p53 maps to the C terminal region, while p53 binding site on Nkx2.5 lies outside its C terminus. In addition, overexpression of Nkx2.5 has a modulatory, promoter dependent effect on p53 transactivation, while the mutant significantly abolished p53 activity on the Mdm2, p21(WAF1/CIP1) and Bax promoters. Their physical interaction contributes to the observed behavior in the case of the Mdm2 promoter. Our data provide a new evidence for the role of p53 in cardiac function through interaction with Nkx2.5.
authors: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia. Electronic address: snezanakojic@imgge.bg.ac.rs.
authors: Snezana
authors: S
authors: Kojic
authors: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
authors: Aleksandra
authors: A
authors: Nestorovic
authors: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
authors: Ljiljana
authors: L
authors: Rakicevic
authors: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia; Faculty of Medicine, Polytechnic University of Marche, Ancona, Italy(1).
authors: Olga
authors: O
authors: Protic
authors: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
authors: Jovana
authors: J
authors: Jasnic-Savovic
authors: CRIBI, University of Padova, Padova, Italy.
authors: Georgine
authors: G
authors: Faulkner
authors: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
authors: Dragica
authors: D
authors: Radojkovic
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002460:Cell Line; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005786:Gene Expression Regulation; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D024510:Muscle Development / Q000235:genetics / Q000502:physiology; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D060066:Protein Interaction Maps; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C432364:ANKRD2 protein, human; C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D050505:Mutant Proteins; C095552:NKX2-5 protein, human; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Ankrd2; Apoptosis; Heart; Nkx2.5; Stress response; p53