PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5

Mrudula Ganga; Herbert M Espinoza; Carol J Cox; Lisa Morton; Tord A Hjalt; Youngsook Lee; Brad A Amendt

doi:10.1074/jbc.M210163200

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PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5

Journal article

Open access

Peer reviewed

PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5

Mrudula Ganga, Herbert M Espinoza, Carol J Cox, Lisa Morton, Tord A Hjalt, Youngsook Lee and Brad A Amendt

The Journal of biological chemistry, Vol.278(25), pp.22437-22445

06/20/2003

DOI: 10.1074/jbc.M210163200

PMID: 12692125

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Abstract

PITX2 and Nkx2.5 are two of the earliest known transcriptional markers of vertebrate heart development. Pitx2-/- mice present with severe cardiac malformations and embryonic lethality, demonstrating a role for PITX2 in heart development. However, little is known about the downstream targets of PITX2 in cardiogenesis. We report here that the atrial natriuretic factor (ANF) promoter is a target of PITX2. PITX2A, PITX2B, and PITX2C isoforms differentially activate the ANF promoter. However, only PITX2C can synergistically activate the ANF promoter in the presence of Nkx2.5. We further demonstrate that the procollagen lysyl hydroxylase (PLOD1) promoter is regulated by Nkx2.5. Mechanistically, PITX2C and Nkx2.5 synergistically regulate ANF and PLOD1 expression through binding to their respective DNA elements. Surprisingly, PITX2A activation of the ANF and PLOD1 promoters is repressed by co-transfection of Nkx2.5 in the C3H10T1/2 embryonic fibroblast cell line. Pitx2a and Pitx2c are endogenously expressed in C3H10T1/2 cells, and these cells express factors that differentially regulate PITX2 isoform activities. We provide a new mechanism for the regulation of heart development by PITX2 isoforms through the regulation of ANF and PLOD1 gene expression and Nkx2.5 transcriptional activity.

Animals

Atrial Natriuretic Factor - genetics

Base Sequence

Cell Line

CHO Cells

Cricetinae

Drug Synergism

Gene Expression Regulation - physiology

Genes, Reporter

Homeobox Protein Nkx-2.5

Homeodomain Proteins - genetics

Homeodomain Proteins - metabolism

Mice

Mice, Knockout

Nuclear Proteins

Polymerase Chain Reaction

Promoter Regions, Genetic

Protein Isoforms - deficiency

Protein Isoforms - genetics

Protein Isoforms - metabolism

Recombinant Fusion Proteins - metabolism

Transcription Factors - deficiency

Transcription Factors - genetics

Transcription Factors - metabolism

Transcription, Genetic

Transfection

Xenopus Proteins

Details

Title: Subtitle: PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5
Creators: Mrudula Ganga - University of Tulsa
Herbert M Espinoza - University of Tulsa
Carol J Cox - University of Tulsa
Lisa Morton - University of Tulsa
Tord A Hjalt - Lund University
Youngsook Lee - University of Wisconsin–Madison
Brad A Amendt - University of Tulsa
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.278(25), pp.22437-22445
DOI: 10.1074/jbc.M210163200
PMID: 12692125
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: 1 R01 DE13941 / NIDCR NIH HHS
Language: English
Date published: 06/20/2003
Academic Unit: Orthodontics; Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984284334302771

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