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Human PRKC Apoptosis WT1 Regulator Is a Novel PITX2-interacting Protein That Regulates PITX2 Transcriptional Activity in Ocular Cells
- Source :
- Journal of Biological Chemistry. 284:34829-34838
- Publication Year :
- 2009
- Publisher :
- Elsevier BV, 2009.
-
Abstract
- Mutations in the homeobox transcription factor PITX2 result in Axenfeld-Rieger syndrome (ARS), which is associated with anterior segment dysgenesis and an increased risk of glaucoma. To understand the pathogenesis of the defects resulting from PITX2 mutations, it is essential to know the normal functions of PITX2 and its interaction with the network of proteins in the eye. Yeast two-hybrid screening was performed using a cDNA library from a human trabecular meshwork primary cell line to detect novel PITX2-interacting proteins and study their role in ARS pathogenesis. After screening of approximately 1 x 10(6) clones, one putative interacting protein was identified named PRKC apoptosis WT1 regulator (PAWR). This interaction was further confirmed by retransformation assay in yeast cells as well as co-immunoprecipitation in ocular cells and nickel pulldown assay in vitro. PAWR is reportedly a proapoptotic protein capable of selectively inducing apoptosis primarily in cancer cells. Our analysis indicates that the homeodomain and the adjacent inhibitory domain in PITX2 interact with the C-terminal leucine zipper domain of PAWR. Endogenous PAWR and PITX2 were found to be located in the nucleus of ocular cells and to co-localize in the mesenchyme of the iridocorneal angle of the developing mouse eye, consistent with a role in the development of the anterior segment of the eye. PAWR was also found to inhibit PITX2 transcriptional activity in ocular cells. These data suggest PAWR is a novel PITX2-interacting protein that regulates PITX2 activity in ocular cells. This information sheds new light in understanding ARS and associated glaucoma pathogenesis.
- Subjects :
- Male
congenital, hereditary, and neonatal diseases and abnormalities
Leucine zipper
Transcription, Genetic
genetic structures
Mesenchyme
Molecular Sequence Data
PAWR
Apoptosis
Biology
Eye
medicine.disease_cause
Biochemistry
Cell Line
Mice
Molecular Basis of Cell and Developmental Biology
Trabecular Meshwork
Two-Hybrid System Techniques
medicine
Animals
Humans
Protein Isoforms
Amino Acid Sequence
Eye Proteins
Molecular Biology
Transcription factor
Homeodomain Proteins
Mutation
Cell Biology
Molecular biology
eye diseases
Mice, Inbred C57BL
stomatognathic diseases
medicine.anatomical_structure
Cancer cell
Homeobox
Female
sense organs
Trabecular meshwork
Apoptosis Regulatory Proteins
Sequence Alignment
Transcription Factors
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 284
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....b5af2b7bef2273581f6de2f36e5c5a61
- Full Text :
- https://doi.org/10.1074/jbc.m109.006684