Cardiac transcription factor Nkx2.5 interacts with p53 and modulates its activity

Snezana Kojic; Aleksandra Nestorovic; Ljiljana Rakicevic; Olga Protic; Jovana Jasnic-Savovic; Georgine Faulkner; Dragica Radojkovic

doi:10.1016/j.abb.2015.02.001

Cardiac transcription factor Nkx2.5 interacts with p53 and modulates its activity

Arch Biochem Biophys. 2015 Mar 1:569:45-53. doi: 10.1016/j.abb.2015.02.001. Epub 2015 Feb 9.

Authors

Snezana Kojic¹, Aleksandra Nestorovic², Ljiljana Rakicevic², Olga Protic³, Jovana Jasnic-Savovic², Georgine Faulkner⁴, Dragica Radojkovic²

Affiliations

¹ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia. Electronic address: snezanakojic@imgge.bg.ac.rs.
² Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
³ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia; Faculty of Medicine, Polytechnic University of Marche, Ancona, Italy(1).
⁴ CRIBI, University of Padova, Padova, Italy.

PMID: 25677450
DOI: 10.1016/j.abb.2015.02.001

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.

Keywords: Ankrd2; Apoptosis; Heart; Nkx2.5; Stress response; p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Binding Sites / genetics
COS Cells
Cell Line
Cell Proliferation
Chlorocebus aethiops
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Gene Expression Regulation
Heart Defects, Congenital / genetics
Heart Defects, Congenital / metabolism
Homeobox Protein Nkx-2.5
Homeodomain Proteins / chemistry
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
Mice
Muscle Development / genetics
Muscle Development / physiology
Muscle Proteins / chemistry
Muscle Proteins / genetics
Muscle Proteins / metabolism
Mutant Proteins / chemistry
Mutant Proteins / genetics
Mutant Proteins / metabolism
Myocardium / metabolism*
Nuclear Proteins / chemistry
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Promoter Regions, Genetic
Protein Interaction Maps
Proto-Oncogene Proteins c-mdm2 / genetics
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Repressor Proteins / chemistry
Repressor Proteins / genetics
Repressor Proteins / metabolism
Transcription Factors / chemistry
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcriptional Activation
Tumor Suppressor Protein p53 / chemistry
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
bcl-2-Associated X Protein / genetics

Substances

ANKRD2 protein, human
BAX protein, human
CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
Homeobox Protein Nkx-2.5
Homeodomain Proteins
Muscle Proteins
Mutant Proteins
NKX2-5 protein, human
Nuclear Proteins
Recombinant Fusion Proteins
Repressor Proteins
TP53 protein, human
Transcription Factors
Tumor Suppressor Protein p53
bcl-2-Associated X Protein
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2